Podcasts about oligodendrocyte

研究領域物換星移，隨著新的研究領域誕生，也有研究領域慢慢淡出人們的視野。而有些曾經冷門的領域，則因為技術進步、新的科學發現，回歸眾人追逐的研究熱點。神經膠質細胞（Neural progenitor cells, NPCs）就是這樣的領域，隨著近年對神經退化疾病的重視，以及全基因組關聯研究（GWAS）的發現指引，原本被認為扮演輔助角色的神經膠質細胞，一躍成為熱門的藥物標的。 本集的訪談邀請到蔡蕙歆博士，他將會介紹神經膠質細胞在神經系統的功能，以及這一群「和神經細胞一樣重要」的細胞，在神經退化疾病領域的進展。此外，蕙歆也會和我們分享他如何轉換領域、挑戰自我，從學界教職跳到業界，從基礎研究進到臨床試驗開發。他也和我們分享管理腦庫的特別經歷、和面對公司人事異動、冷門領域找工作的心法。他談論如何調適心態，應對多變的環境，在職涯中展現的彈性和適應力。相信蕙歆的分享，對於現在面臨嚴峻景氣的求職者，與在職場打拼探索屬於自己的道路的大家，會非常有助益。  

Myelination is one of the last events during mammalian brain development and is thought to continue into young adulthood in humans. Even in adulthood, ongoing low-level myelination is essential for neural homeostasis, and for dynamic processes such as learning and memory. Deficits in myelination resulting in abnormal white matter and disruption of neuronal function are observed in a wide variety of disorders of the CNS. One strategy for alleviating these deficits is to enhance the genesis of myelin-forming oligodendrocytes from their upstream precursor parents, oligodendrocyte precursor cells (OPCs). However, the capability of these OPCs to contribute to remyelination in injury or disease in the adult CNS remains unclear.  To better understand adult oligodendrogenesis and remyelination, our guests today characterized and compared murine OPCs during early postnatal myelination with those from adult injury-induced adult remyelination. Their findings identify two developing OPC groups subserving distinct postnatal functions and suggest that neonatal and adult OPC-mediated oligodendrogenesis are fundamentally different, The findings have important implications for therapeutic interventions aimed at myelin repair. GuestsFreda Miller, PhD, Michael Smith Laboratories, The University of British Columbia Beatrix Wang, BSC, PhD candidate, The University of British Columbia and The University of Toronto Supporting ContentSingle-cell approaches define two groups of mammalian oligodendrocyte precursor cells and their evolution over developmental time, Stem Cell ReportsAbout Stem Cell ReportsStem Cell Reports  is the open access, peer-reviewed journal of the International Society for Stem Cell Research communicating basic discoveries in stem cell research, in addition to translational and clinical studies. Stem Cell Reports  focuses on original research with conceptual or practical advances that are of broad interest to stem cell biologists and clinicians. X: @StemCellReportsAbout ISSCRWith nearly 5,000 members from 75+ countries, the International Society for Stem Cell Research (@ISSCR) is the preeminent global, cross-disciplinary, science-based organization dedicated to stem cell research and its translation to the clinic. The ISSCR mission is to promote excellence in stem cell science and applications to human health.ISSCR StaffKeith Alm, Chief Executive OfficerYvonne Fisher, Managing Editor, Stem Cell ReportsKym Kilbourne, Director of Media and Strategic CommunicationsJack Mosher, Scientific AdvisorVoice WorkBen Snitkoff 

TWiN describes a study that reveals activation of endogenous retroviruses in oligodenroglia from patients with traumatic brain injury.  Hosts: Vincent Racaniello, Jason Shepherd, and Timothy Cheung Subscribe (free): Apple Podcasts, Google Podcasts, RSS Links for this episode MicrobeTV Discord Server Activation of endogenous retroviruses in TBI oligodendroglia (Cell Rep) Timestamps by Jolene. Thanks! Music is by Ronald Jenkees Send your neuroscience questions and comments to twin@microbe.tv

BUFFALO, NY- January 31, 2024 – A new #research paper was #published in Oncotarget's Volume 15 on January 24, 2024, entitled, “BCAS1 defines a heterogeneous cell population in diffuse gliomas.” Oligodendrocyte precursor markers have become of great interest to identify new diagnostic and therapeutic targets for diffuse gliomas, since state-of-the-art studies point towards immature oligodendrocytes as a possible source of gliomagenesis. Brain enriched myelin associated protein 1 (BCAS1) is a novel marker of immature oligodendrocytes and was proposed to contribute to tumorigenesis in non-central nervous system tumors. However, the role of BCAS1 in diffuse glioma is still underexplored. In this new study, researchers Raquel Morales-Gallel, María José Ulloa-Navas, Patricia García-Tárraga, Ricardo Prat-Acín, Gaspar Reynés, Pedro Pérez-Borredá, Luis Rubio, Vivian Capilla-González, Jaime Ferrer-Lozano, and José Manuel García-Verdugo from the University of Valencia-CIBERNED, Mayo Clinic, Hospital Universitari i Politècnic La Fe, University of Pablo de Olavide, and University of Seville-CSIC analyzed the expression of BCAS1 in different tumor samples from patients with diffuse gliomas (17 oligodendrogliomas; 8 astrocytomas; 60 glioblastomas) and uncovered the molecular and ultrastructural features of BCAS1+ cells by immunostaining and electron microscopy. “Our results show that BCAS1+ cells exhibit stellate or spherical morphology with similar ultrastructural features.” Stellate and spherical cells were detected as isolated cells in all studied gliomas. Nevertheless, only stellate cells were found to be proliferative and formed tightly packed nodules with a highly proliferative rate in oligodendrogliomas. Their findings provide a comprehensive characterization of the BCAS1+ cell population within diffuse gliomas. The observed proliferative capacity and distribution of BCAS1+ stellate cells, particularly in oligodendrogliomas, highlight BCAS1 as an interesting marker, warranting further investigation into its role in tumor malignancy. “In conclusion, this insight will shed light on the establishment of BCAS1 as a clinically relevant molecule, serving not only as a diagnostic or prognostic marker but also as a novel therapeutic target for the development of cutting-edge treatments.” DOI - https://doi.org/10.18632/oncotarget.28553 Correspondence to - José Manuel García-Verdugo - j.manuel.garcia@uv.es Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28553 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, brain tumor, diffuse glioma, oligodendroglioma, glioblastoma, BCAS1 About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

A review of neuromyelitis optic spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein associated disease (MOGAD) with Drs. Kevin Yan and Aaron Bower. Note: This podcast is intended solely as an educational tool for learners, especially neurology residents. The contents should not be interpreted as medical advice.Further Reading:Costello F. Neuromyelitis Optica Spectrum Disorders. Continuum (Minneap Minn). 2022 Aug 1;28(4):1131-1170. doi: 10.1212/CON.0000000000001168. Erratum in: Continuum (Minneap Minn). 2022 Dec 1;28(6):1859. PMID: 35938660. Longbrake E. Myelin Oligodendrocyte Glycoprotein-Associated Disorders. Continuum (Minneap Minn). 2022 Aug 1;28(4):1171-1193. doi: 10.1212/CON.0000000000001127. PMID: 35938661; PMCID: PMC9523511.Banwell B, Bennett JL, Marignier R, et al. Diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease: International MOGAD Panel proposed criteria. Lancet Neurol. 2023 Mar;22(3):268-282. doi: 10.1016/S1474-4422(22)00431-8. Epub 2023 Jan 24. PMID: 36706773.

Go online to PeerView.com/CTH860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD) was identified as a distinct demyelinating disease entity only recently. Prior to this characterization of MOGAD, many patients were considered to have a variant of MS, NMOSD, or other neurologic condition. Now an international panel of experts has proposed diagnostic criteria that, when validated, promise to improve MOGAD diagnostic accuracy and confidence. This is particularly important, given that several clinical trials are investigating potential treatments for MOGAD. This unique PeerView activity will use problem-based educational interventions to expose learners to the science and clinical experience behind accurate diagnosis and best practices in management of MOGAD. You will be able to employ optimal clinical decision-making for your patients with MOGAD that is based on the latest evidence, best practice recommendations, and effective interdisciplinary collaboration. Upon completion of this activity, participants should be better able to: Explain the diagnostic criteria for MOGAD as proposed by the International MOGAD Panel; Employ recommended diagnostic tools (eg, the MOG antibody test, relevant MRI findings) to identify MOGAD and distinguish it from other demyelinating diseases; and Implement therapeutic strategies to provide acute treatment and relapse prevention in patients with MOGAD.

Go online to PeerView.com/CTH860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD) was identified as a distinct demyelinating disease entity only recently. Prior to this characterization of MOGAD, many patients were considered to have a variant of MS, NMOSD, or other neurologic condition. Now an international panel of experts has proposed diagnostic criteria that, when validated, promise to improve MOGAD diagnostic accuracy and confidence. This is particularly important, given that several clinical trials are investigating potential treatments for MOGAD. This unique PeerView activity will use problem-based educational interventions to expose learners to the science and clinical experience behind accurate diagnosis and best practices in management of MOGAD. You will be able to employ optimal clinical decision-making for your patients with MOGAD that is based on the latest evidence, best practice recommendations, and effective interdisciplinary collaboration. Upon completion of this activity, participants should be better able to: Explain the diagnostic criteria for MOGAD as proposed by the International MOGAD Panel; Employ recommended diagnostic tools (eg, the MOG antibody test, relevant MRI findings) to identify MOGAD and distinguish it from other demyelinating diseases; and Implement therapeutic strategies to provide acute treatment and relapse prevention in patients with MOGAD.

Go online to PeerView.com/CTH860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD) was identified as a distinct demyelinating disease entity only recently. Prior to this characterization of MOGAD, many patients were considered to have a variant of MS, NMOSD, or other neurologic condition. Now an international panel of experts has proposed diagnostic criteria that, when validated, promise to improve MOGAD diagnostic accuracy and confidence. This is particularly important, given that several clinical trials are investigating potential treatments for MOGAD. This unique PeerView activity will use problem-based educational interventions to expose learners to the science and clinical experience behind accurate diagnosis and best practices in management of MOGAD. You will be able to employ optimal clinical decision-making for your patients with MOGAD that is based on the latest evidence, best practice recommendations, and effective interdisciplinary collaboration. Upon completion of this activity, participants should be better able to: Explain the diagnostic criteria for MOGAD as proposed by the International MOGAD Panel; Employ recommended diagnostic tools (eg, the MOG antibody test, relevant MRI findings) to identify MOGAD and distinguish it from other demyelinating diseases; and Implement therapeutic strategies to provide acute treatment and relapse prevention in patients with MOGAD.

Go online to PeerView.com/CTH860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD) was identified as a distinct demyelinating disease entity only recently. Prior to this characterization of MOGAD, many patients were considered to have a variant of MS, NMOSD, or other neurologic condition. Now an international panel of experts has proposed diagnostic criteria that, when validated, promise to improve MOGAD diagnostic accuracy and confidence. This is particularly important, given that several clinical trials are investigating potential treatments for MOGAD. This unique PeerView activity will use problem-based educational interventions to expose learners to the science and clinical experience behind accurate diagnosis and best practices in management of MOGAD. You will be able to employ optimal clinical decision-making for your patients with MOGAD that is based on the latest evidence, best practice recommendations, and effective interdisciplinary collaboration. Upon completion of this activity, participants should be better able to: Explain the diagnostic criteria for MOGAD as proposed by the International MOGAD Panel; Employ recommended diagnostic tools (eg, the MOG antibody test, relevant MRI findings) to identify MOGAD and distinguish it from other demyelinating diseases; and Implement therapeutic strategies to provide acute treatment and relapse prevention in patients with MOGAD.

Go online to PeerView.com/CTH860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD) was identified as a distinct demyelinating disease entity only recently. Prior to this characterization of MOGAD, many patients were considered to have a variant of MS, NMOSD, or other neurologic condition. Now an international panel of experts has proposed diagnostic criteria that, when validated, promise to improve MOGAD diagnostic accuracy and confidence. This is particularly important, given that several clinical trials are investigating potential treatments for MOGAD. This unique PeerView activity will use problem-based educational interventions to expose learners to the science and clinical experience behind accurate diagnosis and best practices in management of MOGAD. You will be able to employ optimal clinical decision-making for your patients with MOGAD that is based on the latest evidence, best practice recommendations, and effective interdisciplinary collaboration. Upon completion of this activity, participants should be better able to: Explain the diagnostic criteria for MOGAD as proposed by the International MOGAD Panel; Employ recommended diagnostic tools (eg, the MOG antibody test, relevant MRI findings) to identify MOGAD and distinguish it from other demyelinating diseases; and Implement therapeutic strategies to provide acute treatment and relapse prevention in patients with MOGAD.

Go online to PeerView.com/CTH860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD) was identified as a distinct demyelinating disease entity only recently. Prior to this characterization of MOGAD, many patients were considered to have a variant of MS, NMOSD, or other neurologic condition. Now an international panel of experts has proposed diagnostic criteria that, when validated, promise to improve MOGAD diagnostic accuracy and confidence. This is particularly important, given that several clinical trials are investigating potential treatments for MOGAD. This unique PeerView activity will use problem-based educational interventions to expose learners to the science and clinical experience behind accurate diagnosis and best practices in management of MOGAD. You will be able to employ optimal clinical decision-making for your patients with MOGAD that is based on the latest evidence, best practice recommendations, and effective interdisciplinary collaboration. Upon completion of this activity, participants should be better able to: Explain the diagnostic criteria for MOGAD as proposed by the International MOGAD Panel; Employ recommended diagnostic tools (eg, the MOG antibody test, relevant MRI findings) to identify MOGAD and distinguish it from other demyelinating diseases; and Implement therapeutic strategies to provide acute treatment and relapse prevention in patients with MOGAD.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.11.548469v1?rss=1 Authors: Beyer, B. A., Sul, A., Gillen Miller, J. T., Neumann, B., Plaisted, W. C., Kondo, T., Franklin, R. J. M., Lairson, L. L. Abstract: Remyelination-promoting agents have significant potential utility as therapies for the treatment of demyelinating diseases, including multiple sclerosis. Clemastine and bexarotene have recently been evaluated in Phase II clinical trials to evaluate their potential in this context, with evidence for drug-induced remyelination being observed in both trials. Efficacy levels for both agents as monotherapies, as well as dose-limiting toxicities, highlight the need for more effective approaches. Additionally, questions about the relevance of M1R as the target of clemastine, and also around a mechanism involving accumulation of 8,9-unsaturated sterols, remain. Here, we have identified potent alternatives to clemastine (i.e., doxepin and orphenadrine), which are predicted to have superior tolerability and efficacy profiles and provide mechanistic insight related to M1R, and have completed pairwise drug combination screens using diverse classes of OPC differentiation-inducing agents. Vitamin D receptor agonists were found to enhance M1R antagonist-induced OL differentiation. Select compounds implicated in 8,9-unsaturated sterol accumulation synergistically enhanced the activity of bexarotene in OPCs, which resulted in insights that implicate a critical role for liver-X-receptor in the mechanisms of both sterol-dependent and bexarotene-induced remyelination. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Yes, children can get multiple sclerosis. Children ages 12 and up are more typically affected and rarely before age 8. Awareness is essential for prompt diagnosis and treatment of pediatric-onset MS (POMS). Accurate diagnosis of multiple sclerosis in children requires screening for other conditions like MOG antibody-associated disease (MOGAD). Risk factors associated with higher rates of developing MS in kids include Epstein-Barr virus infection, genetic susceptibility, pesticide exposure, smoking (and secondhand smoke), low vitamin D, obesity and diet high in saturated fats. Multiple sclerosis in kids can be very active with frequent relapses and concerning MRI activity kids. Rapid use of highly effective treatment is important to preserve brain health including cognition. Completed and ongoing global pediatric trials are redefining care. Oral fingolimod, for example, reduced relapses by 82% compared to interferon beta-1a injections weekly. Thanks to treatment advancements, teens living with MS have a brighter future ahead of them. Barry Singer MD, Director of The MS Center for Innovations in Care, interviews Brenda Banwell MD, Chief of the Division of Neurology at the Children's Hospital of Philadelphia (CHOP) and Emmanuelle Waubant MD, PhD, Professor of Neurology , University of California San Francisco and Director of the UCSF Regional Pediatric Multiple Sclerosis Center.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.17.537129v1?rss=1 Authors: Hardt, R., Dehghani, A., Schoor, C., Goedderz, M., Cengiz Winter, N., Ahmadi, S., Sharma, R., Schork, K., Eisenacher, M., Gieselmann, V., Winter, D. Abstract: Oligodendrocytes are generated via a two-step mechanism from pluripotent neural stem cells (NSCs): after differentiation of NSCs to oligodendrocyte precursor/NG2 cells (OPCs), they further develop into mature oligodendrocytes. The first step of this differentiation process is only incompletely understood. In this study, we utilized the neurosphere assay to investigate NSC to OPC differentiation in a time course-dependent manner by mass spectrometry-based (phospho-) proteomics. We identify double cortin like kinase 1 (Dclk1) as one of the most prominently regulated proteins in both datasets, and show that it undergoes a gradual transition between its short/long isoform during NSC to OPC differentiation. This is regulated by phosphorylation of its SP-rich region, resulting in inhibition of proteolytic Dclk1 long cleavage, and therefore Dclk1 short generation. Through interactome analyses of different Dclk1 isoforms by proximity biotinylation, we characterize their individual putative interaction partners and substrates. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.17.537139v1?rss=1 Authors: Rusu, B., Kukreja, B., Wu, T., Dan, S. J., Feng, M. Y., Kalish, B. T. Abstract: Down Syndrome (DS), the most common genetic cause of intellectual disability, is associated with lifelong cognitive disability. However, the mechanisms by which triplication of human chromosome 21 genes drive neuroinflammation and cognitive dysfunction are poorly understood. Here, using the Ts65Dn mouse model of DS, we performed an integrated single-nucleus RNA- and ATAC-seq analysis of the cortex. We identify cell type-specific transcriptional and chromatin-associated changes in the Ts65Dn cortex, including regulators of neuroinflammation, transcription and translation, myelination, and mitochondrial function. We discover enrichment of a senescence-associated transcriptional signature in Ts65Dn oligodendrocyte precursor cells (OPCs) and epigenetic changes consistent with a loss of heterochromatin. We find that senescence is restricted to a subset of cortical OPCs concentrated in deep cortical layers. Treatment of Ts65Dn mice with a senescence-reducing flavonoid rescues cortical OPC proliferation, restores microglial homeostasis, and improves contextual fear memory. Together, these findings suggest that cortical OPC senescence may be an important driver of neuropathology in DS. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.11.536299v1?rss=1 Authors: Iyer, M., Kantarci, H., Ambiel, N., Novak, S. W., Andrade, L. R., Lam, M., Munch, A. E., Yu, X., Khakh, B. S., Manor, U. S., Zuchero, J. B. Abstract: Myelin is essential for rapid nerve signaling and is increasingly found to play important roles in learning and in diverse diseases of the CNS. Morphological parameters of myelin such as sheath length and thickness are regulated by neuronal activity and can precisely tune conduction velocity, but the mechanisms controlling sheath morphology are poorly understood. Local calcium signaling has been observed in nascent myelin sheaths and can be modulated by neuronal activity. However, the role of calcium signaling in sheath formation and remodeling is unknown. Here, we used genetic tools to attenuate oligodendrocyte calcium signaling during active myelination in the developing mouse CNS. Surprisingly, we found that genetic calcium attenuation did not grossly affect the number of myelinated axons or myelin thickness. Instead, calcium attenuation caused striking myelination defects resulting in shorter, dysmorphic sheaths. Mechanistically, calcium attenuation reduced actin filaments in oligodendrocytes, and an intact actin cytoskeleton was necessary and sufficient to achieve accurate myelin morphology. Together, our work reveals a novel cellular mechanism required for accurate CNS myelin formation and provides mechanistic insight into how oligodendrocytes may respond to neuronal activity to sculpt myelin sheaths throughout the nervous system. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.19.533192v1?rss=1 Authors: Sajjad, M., Zahoor, I., Rashid, F., Rattan, R., Giri, s. Abstract: The metabolic need of the premature oligodendrocytes (Pre-OLs) and mature oligodendrocytes (OLs) are distinct. The metabolic control of oligodendrocyte maturation is not fully understood. Here we show that the terminal maturation and higher mitochondrial respiration in the oligodendrocyte is an integrated process controlled through pyruvate dehydrogenase (Pdh). Combined bioenergetics and metabolic studies show that mature oligodendrocytes show elevated TCA cycle activity than the premature oligodendrocytes. Our signaling studies show that the increased TCA cycle activity is mediated by the activation of Pdh due to inhibition of pyruvate dehydrogenases isoform-1 (Pdhk1) that phosphorylates and inhibits Pdh. Accordingly, when Pdhk1 is directly expressed in the premature oligodendrocytes, they fail to mature. While Pdh converts pyruvate into the acetyl-CoA by its oxidative decarboxylation, our study shows that Pdh also activates a unique molecular switch required for oligodendrocyte maturation by acetylating the bHLH family transcription factor Olig1. Pdh inhibition via Pdhk1 blocks the Olig1-acetylation and hence, oligodendrocyte maturation. Using the cuprizone model of demyelination, we show that Pdh is deactivated during the demyelination phase, which is reversed in the remyelination phase upon cuprizone withdrawal. In addition, Pdh activity status correlates with the Olig1-acetylation status. Hence, the Pdh metabolic node activation allows a robust mitochondrial respiration and activation of a molecular program necessary for the terminal maturation of oligodendrocytes. Our findings open a new dialogue in the developmental biology that links cellular development and metabolism. These findings have far-reaching implications for the development of therapies for a variety of demyelinating disorders including multiple sclerosis. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Dr. Sara Mariotto discusses her paper, "Significance of Myelin Oligodendrocyte Glycoprotein Antibodies in CSF: A Retrospective Multicenter Study". Show references: https://n.neurology.org/content/early/2022/12/16/WNL.0000000000201662

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.17.529003v1?rss=1 Authors: Sutter, P. A., Willis, C. M., Menoret, A., Nicaise, A. M., Sacino, A. V., Sikkema, A. H., Jellison, E. R., Win, K. K., Han, D. K., Church, W., Baron, W., Vella, A. T. J., Crocker, S. J. Abstract: Astrocyte activation is associated with neuropathology and the production of tissue inhibitor of metalloproteinase-1 (TIMP1). TIMP1 is a pleiotropic extracellular protein that functions both as a protease inhibitor and as a growth factor. We have previously demonstrated that murine astrocytes that lack expression of Timp1 do not support rat oligodendrocyte progenitor cell (rOPC) differentiation, and adult global Timp1 knockout (Timp1KO) mice do not efficiently remyelinate following a demyelinating injury. To better understand the basis of this, we performed unbiased proteomic analyses and identified a fibronectin-derived peptide called anastellin that is unique to the murine Timp1KO astrocyte secretome. Anastellin was found to block rOPC differentiation in vitro and enhanced the inhibitory influence of fibronectin on rOPC differentiation. Anastellin is known to act upon the sphingosine-1-phosphate receptor 1 (S1PR1), and we determined that anastellin also blocked the pro-myelinating effect of FTY720 (or fingolimod) on rOPC differentiation in vitro. Further, administration of FTY720 to wild-type C57BL/6 mice during MOG35-55-EAE ameliorated clinical disability while FTY720 administered to mice lacking expression of Timp1 in astrocytes (Timp1cKO) had no effect. Analysis of human TIMP1 and fibronectin (FN1) transcripts from healthy and multiple sclerosis (MS) patient brain samples revealed an inverse relationship where lower TIMP1 expression was coincident with elevated FN1 in MS astrocytes. Lastly, we analyzed proteomic databases of MS samples and identified anastellin peptides to be more abundant in the cerebrospinal fluid (CSF) of human MS patients with high versus low disease activity. The prospective role for anastellin generation in association with myelin lesions as a consequence of a lack of astrocytic TIMP-1 production could influence both the efficacy of fingolimod responses and the innate remyelination potential of the the MS brain. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.10.528042v1?rss=1 Authors: Cohn, E. F., Clayton, B. L. L., Madhavan, M., Yacoub, S., Federov, Y., Paul-Friedman, K., Shafer, T. J., Tesar, P. Abstract: Exposure to environmental chemicals can impair neurodevelopment. Oligodendrocytes that wrap around axons to boost neurotransmission may be particularly vulnerable to chemical toxicity as they develop throughout fetal development and into adulthood. However, few environmental chemicals have been assessed for potential risks to oligodendrocyte development. Here, we utilized a high-throughput developmental screen and human cortical brain organoids, which revealed environmental chemicals in two classes that disrupt oligodendrocyte development through distinct mechanisms. Quaternary compounds, ubiquitous in disinfecting agents, hair conditioners, and fabric softeners, were potently and selectively cytotoxic to developing oligodendrocytes through activation of the integrated stress response. Organophosphate flame retardants, commonly found in household items such as furniture and electronics, were non-cytotoxic but prematurely arrested oligodendrocyte maturation. Chemicals from each class impaired human oligodendrocyte development in a 3D organoid model of prenatal cortical development. In analysis of epidemiological data from the CDC's National Health and Nutrition Examination Survey, adverse neurodevelopmental outcomes were associated with childhood exposure to the top organophosphate flame retardant identified by our oligodendrocyte toxicity platform. Collectively, our work identifies toxicological vulnerabilities specific to oligodendrocyte development and highlights common household chemicals with high exposure risk to children that warrant deeper scrutiny for their impact on human health. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.05.522879v1?rss=1 Authors: Frazier, A. P., Mitchell, D. N., Given, K. S., Burch, A. M., Childs, C. R., Moreno-Garcia, M., Corigliano, M. R., Quillinan, N., Macklin, W. B., Herson, P., Dingman, A. Abstract: Background: Neonatal stroke is common and causes life-long motor and cognitive sequelae. Because neonates with stroke are not diagnosed until days-months after the injury, chronic targets for repair are needed. We evaluated oligodendrocyte maturity and myelination and assessed oligodendrocyte gene expression changes using single cell RNA sequencing (scRNA seq) at chronic timepoints in a mouse model of neonatal arterial ischemic stroke. Methods: Mice underwent sixty minutes of transient right middle cerebral artery occlusion (MCAO) on postnatal day 10 (p10) and received 5-ethynyl-2'-deoxyuridine (EdU) on post-MCAO days 3-7 to label dividing cells. Animals were sacrificed 14 and 28-30 days post-MCAO for immunohistochemistry and electron microscopy. Oligodendrocytes were isolated from striatum 14 days post-MCAO for scRNA seq and differential gene expression analysis. Results: The density of Olig2+EdU+ cells was significantly increased in ipsilateral striatum 14 days post-MCAO and the majority of oligodendrocytes were immature. Density of Olig2+EdU+ cells declined significantly between 14 and 28 days post-MCAO without a concurrent increase in mature Olig2+EdU+ cells. By 28 days post-MCAO there were significantly fewer myelinated axons in ipsilateral striatum. scRNA seq identified a cluster of disease associated oligodendrocytes (DOLs) specific to the ischemic striatum, with increased expression of MHC class I genes. Gene ontology analysis suggested decreased enrichment of pathways involved in myelin production in the reactive cluster. Conclusions: Oligodendrocytes proliferate 3-7 days post-MCAO and persist at 14 days, but fail to mature by 28 days. MCAO induces a subset of oligodendrocytes with reactive phenotype, which may be a therapeutic target to promote white matter repair. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.31.522394v1?rss=1 Authors: Zhang, T., Bae, H.-G., Bhambri, A., Zhang, Y., Barbosa, D., Xue, J., Wazir, S., Mulinyawe, S. B., Kim, J. H., Sun, L. O. Abstract: Oligodendrocytes are the sole myelin producing cells in the central nervous system. Oligodendrocyte numbers are tightly controlled across diverse brain regions to match local axon type and number, but the underlying mechanisms and functional significance remain unclear. Here, we show that autophagy, an evolutionarily conserved cellular process that promotes cell survival under canonical settings, elicits premyelinating oligodendrocyte apoptosis during development and regulates critical aspects of nerve pulse propagation. Autophagy flux is increased in premyelinating oligodendrocytes, and its genetic blockage causes ectopic oligodendrocyte survival throughout the entire brain. Autophagy acts in the TFEB-Bax/Bak pathway and elevates PUMA mRNA levels to trigger premyelinating oligodendrocyte apoptosis cell-autonomously. Autophagy continuously functions in the myelinating oligodendrocytes to limit myelin sheath numbers and fine-tune nerve pulse propagation. Our results provide in vivo evidence showing that autophagy promotes apoptosis in mammalian cells under physiological conditions and reveal key intrinsic mechanisms governing oligodendrocyte number. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.08.515614v1?rss=1 Authors: Looser, Z. J., Ravotto, L., Jung, R. B., Werner, H. B., Ruhwedel, T., Moebius, W., Bergles, D. E., Barros, L. F., Nave, K.-A., Weber, B., Saab, A. S. Abstract: The integrity of myelinated axons relies on homeostatic support from oligodendrocytes (OLs), which is essential for brain function. However, the mechanisms by which OLs detect axonal spiking and rapidly control axon-OL metabolic coupling are largely unknown. Here, we combine optic nerve electrophysiology and two-photon imaging to study activity-dependent calcium (Ca2+) dynamics in OLs and metabolite fluxes in myelinated axons. Both high-frequency axonal firing and extracellular potassium (K+) elevations trigger a fast Ca2+ response in OLs that is facilitated by barium-sensitive, inwardly rectifying K+ channels. Using OL-specific Kir4.1 knockout mice (Kir4.1 cKO) we now demonstrate that, in addition to being crucial for K+ clearance, oligodendroglial Kir4.1 regulates axonal energy metabolism and long-term axonal integrity. Before the manifestation of axonal damage, we observed reduced glucose transporter GLUT1 and monocarboxylate transporter MCT1 expression in myelin of young Kir4.1 cKO mice, suggesting early deficits in metabolite supply to axons. Strikingly, we found lower resting lactate levels and activity-induced lactate surges in optic nerve axons of young Kir4.1 cKO mice. Moreover, both axonal glucose uptake and consumption were hampered in the absence of oligodendroglial Kir4.1, uncovering a new role of OLs in regulating axonal glucose metabolism. Our findings reveal a novel model of axon-OL signaling and metabolic coupling in which OLs detect high-frequency axonal activity through K+ signaling, which is critical in adjusting the axon-OL metabolic unit and in preserving long-term axonal health. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.12.511898v1?rss=1 Authors: Siletti, K., Hodge, R. D., Mossi Albiach, A., Hu, L., Lee, K. W., Lönnerberg, P., Bakken, T. E., Ding, S.-L., Clark, M., Casper, T., Dee, N., Gloe, J., Keene, C. D., Nyhus, J., Tung, H., Yanny, A. M., Arenas, E., Lein, E. S., Linnarsson, S. Abstract: The human brain directs a wide range of complex behaviors ranging from fine motor skills to abstract intelligence and emotion. However, the diversity of cell types that support these skills has not been fully described. Here we used high-throughput single-nucleus RNA sequencing to systematically survey cells across the entire adult human brain in three postmortem donors. We sampled over three million nuclei from approximately 100 dissections across the forebrain, midbrain, and hindbrain. Our analysis identified 461 clusters and 3313 subclusters organized largely according to developmental origins. We found area-specific cortical neurons, as well as an unexpectedly high diversity of midbrain and hindbrain neurons. Astrocytes also exhibited regional diversity at multiple scales, comprising subtypes specific to the telencephalon and to more precise anatomical locations. Oligodendrocyte precursors comprised two distinct major types specific to the telencephalon and to the rest of the brain. Together, these findings demonstrate the unique cellular composition of the telencephalon with respect to all major brain cell types. As the first single-cell transcriptomic census of the entire human brain, we provide a resource for understanding the molecular diversity of the human brain in health and disease. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.04.510850v1?rss=1 Authors: Molina-Gonzalez, I., Holloway, R. K., Jiwaji, Z., Dando, O. R., Emelianova, K., Lloyd, A. F., Forbes, L. H., Mahmood, A., Skripuletz, T., Gudi, V., Febery, J., Johnson, J., Fowler, J., Kuhlmann, T., Williams, A., Chandran, S., Stangel, M., Howden, A. J., Hardingham, G., Miron, V. E. Abstract: Failed regeneration of myelin around neuronal axons following central nervous system damage contributes to nerve dysfunction and clinical decline in various neurological conditions, for which there is an unmet therapeutic demand. Here, we show that interaction between glial cells, astrocytes and mature myelin-forming oligodendrocytes, is a critical determinant of remyelination. Astrocytes support the survival of regenerating oligodendrocytes, via downregulation of the Nrf2 pathway associated with increased astrocytic cholesterol biosynthesis pathway activation. Remyelination fails following sustained astrocytic Nrf2 activation yet is restored by either cholesterol biosynthesis/efflux stimulation, or Nrf2 inhibition using the existing therapeutic Luteolin. We identify that astrocyte-oligodendrocyte interaction regulates remyelination, and reveal a drug strategy for central nervous system regeneration centred on targeting this interaction. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.28.509944v1?rss=1 Authors: Kim, H., Skuba, A., Xia, J., Han, S. B., Zhai, J., Yoo, R., Hu, H., Kang, S. H., Son, Y.-J. Abstract: Adult mammalian spinal cord stops re-entering sensory axons, resulting in incurable sensory loss after dorsal root injury. Challenging the prevailing view, we previously showed that axons rapidly stop by forming synaptic, not dystrophic endings, and that myelin inhibitors and CSPGs are not the primary mechanism arresting axons. Here, we report that in adult mice dystrophic endings are formed by occasional axons embedded in fibrous collagens, exclusively at the CNS:PNS boundary where oligodendrocyte precursor cells (OPCs, or NG2 glia) are sparse. Most axons stop beyond the boundary in extensive contacts with OPC processes. Live imaging, immuno-EM and OPC-DRG co-culture show that axonal synapses form on OPCs. Genetic OPC ablation, although incomplete, enables many axons to continue regenerating deep into the spinal cord. These data, together with earlier findings, conclusively demonstrate that axons stop largely because OPCs stimulate presynaptic differentiation. We identify OPCs as a major regenerative barrier at the CNS:PNS border. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.21.508765v1?rss=1 Authors: Iram, T., Garcia, M. A., Amand, J., Kaur, A., Iyer, M., Lam, M., Ambiel, N., Keller, A., Wyss-Coray, T., Kern, F., Zuchero, J. B. Abstract: Myelination of neuronal axons is essential for nervous system development. Myelination requires dramatic cytoskeletal dynamics in oligodendrocytes, but how actin is regulated during myelination is poorly understood. We recently identified serum response factor (SRF), a transcription factor known to regulate expression of actin and actin regulators in other cell types, as a critical driver of myelination in the aged brain. Yet, a major gap remains in understanding the fundamental role of SRF in oligodendrocyte lineage cells. Here we show that SRF is required cell autonomously in oligodendrocytes for myelination during development. Combining ChIP-seq with RNA-seq identifies SRF-target genes in OPCs and oligodendrocytes that include actin and other key cytoskeletal genes. Accordingly, SRF knockout oligodendrocytes exhibit dramatically reduced actin filament levels early in differentiation, consistent with its role in actin-dependent myelin sheath initiation. Together, our findings identify SRF as a transcriptional regulator that controls the expression of cytoskeletal genes required in oligodendrocytes for myelination. This study identifies a novel pathway regulating oligodendrocyte biology with high relevance to brain development, aging, and disease. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Dr. Melissa Wright discusses her abstract, "MOGAD in the Mountain West: Epidemiology and Outcomes in Pediatric and Adult Patients at Two Large Academic Referral Centers". You can find Dr. Wright's abstract, along with all of our summer conference abstracts here: https://www.aan.com/MSA/Public/Events/Index/44 This podcast is sponsored by argenx. Visit www.vyvgarthcp.com for more information.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.10.507429v1?rss=1 Authors: Fekete, C. D., Horning, R. Z., Doron, M. S., Nishiyama, A. Abstract: In the developing and adult CNS, new oligodendrocytes (OLs) are generated from a population of cells known as oligodendrocyte precursor cells (OPCs). As they begin to differentiate, OPCs undergo a series of highly regulated changes to morphology, gene expression, and membrane organization. This stage represents a critical bottleneck in oligodendrogenesis, and the regulatory program that guides it is still not fully understood. Here we show that in vivo toxin-mediated cleavage of the vesicle associated SNARE proteins VAMP2/3 in the OL lineage of both male and female mice impairs the ability of early OLs to mature into functional, myelinating OLs. In the developing mouse spinal cord, many VAMP2/3-deficient OLs appeared to stall in the premyelinating, early OL stage, resulting in an overall loss of both myelin density and OL number. The Src kinase Fyn, a key regulator of oligodendrogenesis and myelination, is highly expressed among premyelinating OLs, but its expression decreases as OLs mature. We found that OLs lacking VAMP2/3 in the spinal cord white matter showed significantly higher expression of Fyn compared to neighboring control cells, potentially due to an extended premyelinating stage. Overall, our results show that functional VAMP2/3 in OL lineage cells is essential for proper myelin formation and plays a major role in controlling the maturation and terminal differentiation of premyelinating OLs. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.31.505555v1?rss=1 Authors: Fiore, F., Dereddi, R. R., Alhalaseh, K., Coban, I., Harb, A., Agarwal, A. Abstract: Oligodendrocyte precursor cells (OPCs) represent the most abundant group of proliferating cells in the adult central nervous system. OPCs serve as progenitors for oligodendrocyte (OLs) throughout the life, and contribute to developmental and adaptive myelination, and myelin repair during diseased state. OPCs make synaptic and extra-synaptic contacts with axons, and detect and respond to neuronal activity. How OPCs translate the information relayed by the neuronal activity into Ca2+ signals, which in turn influence their fate and survival, is less understood. We developed novel transgenic mouse lines expressing a cytosolic and membrane anchored variants of genetically encoded Ca2+ sensors (GCaMP6f or mGCaMP6s) in OPCs, performed 2-photon microscopy in the somatosensory cortex of the awake behaving mice, and simultaneously monitored intracellular Ca2+ signals and their cell-fate progression. We found Ca2+ signals in OPCs mainly occur within processes and confine to micrometer-size segments called Ca2+ microdomains. Microdomain Ca2+ signals enhanced in OPCs when mice engage in exploratory behavior. OPCs exhibit distinct Ca2+ signals while they proliferate to maintain their precursor pool or differentiate to generate new OL. When mice engaged in exploratory behavior, the cortical projections of noradrenergic neurons in locus coeruleus showed increased firing rate and norepinephrine release. Norepinephrine activated all three subtypes of alpha1 adrenergic receptor expressed by OPCs and evoked intracellular Ca2+ increase in OPCs. A chemogenetic activation of noradrenergic neurons, promoted differentiation of cortical OPCs into OL, and at the same time suppressed OPC proliferation rate. Hence, we uncovered that various cell types of oligodendrocyte lineage exhibits unique signatures of Ca2+ activity, which these cells might integrate for making their fate decisions, and norepinephrine signaling can be a potent regulator of OPC fate. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.25.505119v1?rss=1 Authors: Lu, T.-Y., Hanumaihgari, P., Hsu, E. T., Agarwal, A., Bergles, D. E. Abstract: Oligodendrocytes are generated from a widely distributed population of progenitors that express neurotransmitter receptors, but the mechanisms that alter activity of these oligodendrocyte precursor cells (OPCs) in vivo have not been determined. We generated a novel line of transgenic mice to express membrane-anchored GCaMP6s in OPCs and used longitudinal two-photon microscopy to monitor their calcium changes in the cerebral cortex of awake mice. OPCs exhibited high rates of spontaneous activity, consisting of focal, transient calcium increases within their highly ramified processes. Unexpectedly, these events occurred independent of excitatory neuron activity, but were inhibited by anesthesia, sedative agents, and antagonists of noradrenergic signaling. These norepinephrine enhanced calcium dynamics rapidly declined as with differentiation. Selective knockout of alpha-1A adrenergic receptors in OPCs suppressed both spontaneous and locomotion-induced calcium increases, indicating that OPCs are directly modulated by norepinephrine in vivo, providing a means to alter their dynamics and lineage progression during distinct brain states. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

In part 3 of a 3-part series, Erin Longbrake, MD, Ph.D., FAAN, discusses her article, "Myelin Oligodendrocyte Glycoprotein–Associated Disorders" from the Continuum August Multiple Sclerosis and Related Disorders issue. This article and the accompanying Continuum Audio interview are available to subscribers at continpub.com/MOGAD. This podcast is sponsored by argenx. Visit www.vyvgarthcp.com for more information.

In part 2 of a 3-part series, Erin Longbrake, MD, PhD, FAAN, discusses her article, "Myelin Oligodendrocyte Glycoprotein–Associated Disorders" from the Continuum August Multiple Sclerosis and Related Disorders issue. This article and the accompanying Continuum Audio interview are available to subscribers at continpub.com/MOGAD. This podcast is sponsored by argenx. Visit www.vyvgarthcp.com for more information.

In part 1 of a 3-part series, Erin Longbrake, MD, PhD, FAAN, discusses her article, "Myelin Oligodendrocyte Glycoprotein–Associated Disorders" from the Continuum August Multiple Sclerosis and Related Disorders issue. This article and the accompanying Continuum Audio interview are available to subscribers at continpub.com/MOGAD. This podcast is sponsored by argenx. Visit www.vyvgarthcp.com for more information.

In this episode of the Epigenetics Podcast, we caught up with Goncalo Castelo-Branco from the Karolinska Institute to talk about his work on the characterization of epigenetic states in the Oligodendrocyte Lineage. The group from Gonçalo Castelo-Branco's lab focuses on characterizing epigenetic states of oligodendrocytes, with the aim to understand their contribution to diseases like multiple sclerosis. To do this the group used single-cell RNA-Seq to identify sub-populations of oligodendrocytes. Furthermore, the team pioneered improvements in CUT&Tag and applied it to the single-cell space, as well as developing spatial CUT&Tag. More recently they used nanobodies in an optimised version of single cell CUT&Tag that allows simultaneous probing of three epigenomic modalities at single-cell resolution, using nanobody-Tn5 fusion proteins. The three modalities encompass chromatin accessibility as measured via ATAC-Seq and two histone post-transcriptional modifications.   References Deng Y, Bartosovic M, Kukanja P, Zhang D, Liu Y, Su G, Enninful A, Bai Z, Castelo-Branco G, Fan R. Spatial-CUT&Tag: Spatially resolved chromatin modification profiling at the cellular level. Science. 2022 Feb 11;375(6581):681-686. doi: 10.1126/science.abg7216. Epub 2022 Feb 10. PMID: 35143307. Winick-Ng W, Kukalev A, Harabula I, Zea-Redondo L, Szabó D, Meijer M, Serebreni L, Zhang Y, Bianco S, Chiariello AM, Irastorza-Azcarate I, Thieme CJ, Sparks TM, Carvalho S, Fiorillo L, Musella F, Irani E, Torlai Triglia E, Kolodziejczyk AA, Abentung A, Apostolova G, Paul EJ, Franke V, Kempfer R, Akalin A, Teichmann SA, Dechant G, Ungless MA, Nicodemi M, Welch L, Castelo-Branco G, Pombo A. Cell-type specialization is encoded by specific chromatin topologies. Nature. 2021 Nov;599(7886):684-691. doi: 10.1038/s41586-021-04081-2. Epub 2021 Nov 17. PMID: 34789882; PMCID: PMC8612935. Bartosovic M, Kabbe M, Castelo-Branco G. Single-cell CUT&Tag profiles histone modifications and transcription factors in complex tissues. Nat Biotechnol. 2021 Jul;39(7):825-835. doi: 10.1038/s41587-021-00869-9. Epub 2021 Apr 12. PMID: 33846645; PMCID: PMC7611252. Marek Bartosovic, Gonçalo Castelo-Branco. Multimodal chromatin profiling using nanobody-based single-cell CUT&Tag. bioRxiv. 2022.03.08.483459; doi: https://doi.org/10.1101/2022.03.08.483459   Related Episodes Multiple challenges of CUT&Tag (Cassidee McDonough, Kyle Tanguay) Chromatin Profiling: From ChIP to CUT&RUN, CUT&Tag and CUTAC (Steven Henikoff)   Contact Active Motif on Twitter Epigenetics Podcast on Twitter Active Motif on LinkedIn Active Motif on Facebook Email: podcast@activemotif.com

Dr. Rae Bacharach discusses the Neurology Today article, "Maintenance Intravenous Immunoglobulin Prevents Relapse in Adult Myelin Oligodendrocyte Glycoprotein Antibody–Associated Disease". Show references: https://journals.lww.com/neurotodayonline/Fulltext/2022/05190/Maintenance_Intravenous_Immunoglobulin_Prevents.1.aspx

TWiN reveals how oligodendrocytes enhance axonal energy metabolism by transcellular delivery of a protein, SIRT2, that deacetylates mitochondrial proteins. Hosts: Vincent Racaniello, Timothy Cheung, and Vivianne Morrison Click arrow to play Download TWiN 028 (77 MB .mp3, 64 min) Subscribe (free): Apple Podcasts, Google Podcasts, RSS, email Become a patron of TWiN! Links for this episode Glia 101 (TWiN 19) Oligodendrocytes enhance axonal energy metabolism (Neuron) Timestamps by Jolene. Thanks! Music is by Ronald Jenkees Send your neuroscience questions and comments to twin@microbe.tv

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.10.377226v1?rss=1 Authors: Hu, X., Xiao, G., He, L., Niu, X., Li, H., Xu, Q., Wei, Z., Qiu, M., Tanaka, K. F., Shen, Y., Tao, Y. Abstract: Oligodendrocytes are vulnerable to genetic and environmental insults and its injury leads to demyelinating diseases. The roles of ErbB receptors in the CNS myelin integrity are largely unknown. Here we overactivate ErbB receptors that mediate signaling of either neuregulin or EGF family growth factors and found their synergistic activation caused deleterious outcomes in white matter. Sustained ErbB activation induced by the tetracycline-dependent mouse tool Plp-tTA resulted in demyelination, axonal degeneration, oligodendrocyte precursor cell (OPC) proliferation, astrogliosis, and microgliosis in white matter. Moreover, there was hypermyelination prior to these pathological events. In contrast, sustained ErbB activation induced by another tetracycline-dependent mouse tool Sox10+/rtTA caused hypomyelination in the corpus callosum and optic nerve, which appeared to be a developmental deficit and did not associate with OPC regeneration, astrogliosis, or microgliosis. By analyzing the differentiation states of cells that were pulse-labeled with a viral reporter, we found that, during juvenile to adolescent development, Plp-tTA targeted mainly mature oligodendrocytes (MOs), while Sox10+/rtTA targeted OPCs and newly-formed oligodendrocytes. The distinct phenotypes of mice with ErbB overactivation induced by Plp-tTA and Sox10+/rtTA supported the reporter pulse-labeling results, and consolidated their non-overlapping targeting preferences in the oligodendrocyte lineage after early development. These features enabled us to demonstrate that ErbB overactivation in MOs induced necroptosis that caused pathological demyelination, whereas in OPCs induced apoptosis that caused developmental hypomyelination. These results established an upstream pathogenic role of ErbB overactivation in oligodendrocytes, providing molecular and cellular insights into the primary oligodendropathy in demyelinating diseases. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.07.356311v1?rss=1 Authors: Shen, S., Wang, Y., Xia, R., Zeng, F., Cao, J., Liu, X., Zhang, Y., Wang, Z., Tao, T. Abstract: The cell type-specific molecular pathology of post-stroke cognitive impairment (PSCI) in the hippocampus has not been thoroughly elucidated. We analyzed 27,069 cells by using single-cell RNA sequencing, and four oligodendrocyte precursor cell (OPC) subtypes were identified, Vcan+ OPCs, which were determined to be the primary cluster among them. Additionally, we examined the features of endothelial cells (ECs) and found that Lcn2+ ECs might play neuroprotective roles via Vwf after stroke. These results may facilitate further studies attempting to identify new avenues of research and novel targets for PSCI treatment. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.09.374306v1?rss=1 Authors: Mazuir, E., Richevaux, L., Nassar, M., Robil, N., de la Grange, P., Lubetzki, C., Fricker, D., Sol-Foulon, N. Abstract: Oligodendrocytes form myelin for central nervous system axons and release factors which signal to neurons during myelination. Here, we ask how oligodendroglial factors influence hippocampal GABAergic neuron physiology. In mixed hippocampal cultures GABAergic neurons fired action potentials of short duration and received high frequencies of excitatory synaptic events. In purified neuronal cultures without glial cells, GABAergic neuron excitability increased and the frequency of synaptic events decreased. These effects were largely reversed by adding oligodendrocyte conditioned medium. We compared the transcriptomic signature with the electrophysiological phenotype of single neurons in these three culture conditions. Genes expressed by single pyramidal or GABAergic neurons largely conformed to expected cell-type specific patterns. Multiple genes of GABAergic neurons were significantly downregulated by the transition from mixed cultures containing glial cells to purified neuronal cultures. Levels of these genes were restored by the addition of oligodendrocyte conditioned medium to purified cultures. Clustering genes with similar changes in expression between different culture conditions revealed processes affected by oligodendroglial factors. Enriched genes are linked to roles in synapse assembly, action potential generation and transmembrane ion transport, including of zinc. These results provide new insight into the molecular targets by which oligodendrocytes influence neuron excitability and synaptic function. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.27.357244v1?rss=1 Authors: Zhou, H., He, Y., Yang, Y., Wang, Z., Wang, Q., Hu, C., Wang, X., Lu, S., Li, K., Luan, Z. Abstract: NG2 and A2B5 are important biological markers of human oligodendrocyte progenitor cells. To study their functional differences during the development of human oligodendrocyte progenitor cells to oligodendrocytes, we used cell sorting technology and obtained a large number of sterile, high-purity NG2+/- and A2B5+/- cells with high viability. Further research was then conducted via in vitro cell proliferation and migration assays, single-cell sequencing, mRNA sequencing, and cell transplantation into shiverer mice. The results showed that the migration ability of the cells was inversely proportional to the myelination ability. NG2 may be a marker of early oligodendrocyte progenitor cells and is conducive to cell migration and proliferation, while A2B5 may be a marker of slightly mature oligodendrocyte progenitor cells and is conducive to cell differentiation. Further, cell migration, proliferation, and myelination capacity of the negative cell population were stronger than those of the positive cell population. In summary, these results suggest that oligodendrocyte progenitor cells in the mid-stage may be more suitable for clinical cell transplantation to treat demyelinating diseases. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.26.354746v1?rss=1 Authors: Rivera, A. D., Pieropan, F., Chacon De La Rocha, I., Lecca, D., Abbracchio, M. P., Azim, K., Butt, A. M. Abstract: Brain aging is characterised by a decline in neuronal function and associated cognitive deficits. There is increasing evidence that myelin disruption is an important factor that contributes to the age-related loss of brain plasticity and repair responses. In the brain, myelin is produced by oligodendrocytes, which are generated throughout life by oligodendrocyte progenitor cells (OPCs). Currently, a leading hypothesis points to aging as a major reason for the ultimate breakdown of remyelination in Multiple Sclerosis (MS). However, an incomplete understanding of the cellular and molecular processes underlying brain aging hinders the development of regenerative strategies. Here, our combined systems biology and neurobiological approach demonstrates that oligodendroglial and myelin genes are amongst the most altered in the aging mouse cortex. This was underscored by the identification of causal links between signaling pathways and their downstream transcriptional networks that define oligodendroglial disruption in aging. The results highlighted that the G-protein coupled receptor GPR17 is central to the disruption of OPC in aging and this was confirmed by genetic fate mapping and cellular analyses. Finally, we used systems biology strategies to identify therapeutic agents that rejuvenate OPC and restore myelination in age-related neuropathological contexts. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.22.349209v1?rss=1 Authors: Khandker, L., Jeffries, M. A., Chang, Y.-J., Mather, M. L., Bourne, J. N., Tafreshi, A. K., Bozdagi-Gunal, O., Macklin, W. B., Wood, T. L. Abstract: Brain and spinal cord oligodendroglia have distinct functional characteristics, and cell autonomous loss of individual genes can result in different regional phenotypes. However, sequencing studies to date have not revealed distinctions between brain and spinal cord oligodendroglia. Using single-cell analysis of oligodendroglia during myelination, we demonstrate that brain and spinal cord precursors are transcriptionally distinct, defined predominantly by cholesterol biosynthesis. We further identify mechanistic target of rapamycin (mTOR) as a major regulator promoting cholesterol biosynthesis in oligodendroglia. Oligodendroglial-specific loss of mTOR compromises cholesterol biosynthesis in both the brain and spinal cord. Importantly, mTOR loss has a greater impact on cholesterol biosynthesis in spinal cord oligodendroglia that corresponds with more pronounced developmental deficits. However, loss of mTOR in brain oligodendroglia ultimately results in oligodendrocyte death, spontaneous demyelination, and impaired axonal function, demonstrating that mTOR is required for myelin maintenance in the adult brain. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.19.345355v1?rss=1 Authors: Tanti, A., Belliveau, C., Nagy, C., Maitra, M., Denux, F., Perlman, K., Chen, F., Mpai, R., Canonne, C., Davoli, M.-A., Turecki, G., Mechawar, N. Abstract: Child abuse (CA) is a strong predictor of psychopathologies and suicide, and can lastingly alter normal trajectories of brain development, in particular in areas closely linked to emotional responses such as the prefrontal cortex (PFC). Yet, the cellular underpinnings of these enduring effects are unclear. Childhood and adolescence are marked by the protracted formation of perineuronal nets (PNNs), which are essential in orchestrating the closure of developmental windows of cortical plasticity by regulating the functional integration of parvalbumin interneurons (PV) into neuronal circuits. Using well-characterized post-mortem brain samples, we explored the hypothesis that CA has lasting effects on the development of PNNs in the ventromedial PFC. We found that a history of CA was specifically associated with increased recruitment and maturation of PNNs. Through single-nucleus sequencing and fluorescent in-situ hybridization, we provide evidence for the involvement of oligodendrocyte progenitor cells (OPCs) in this phenomenon by showing that the expression of canonical components of PNNs are highly enriched and upregulated in this cell type in CA victims. These findings suggest that early-life adversity may lead to persistent patterns of maladaptive behaviours by reducing the neuroplasticity of cortical circuits through the enhancement of developmental OPC-mediated PNN formation. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.07.328971v1?rss=1 Authors: Chamling, X., Kallman, A., Berlinicke, C., Devkota, P., Mertz, J. L., Chang, C., Kaushik, A., Chen, L., Calabresi, P., Mao, H.-Q., Wang, J. T.-H., Zack, D. Abstract: Injury and loss of oligodendrocytes can cause demyelinating diseases such as multiple sclerosis. To improve our understanding of oligodendrocyte development, which could facilitate development of remyelination-based treatment strategies, we performed single-cell- transcriptomic-analysis of developing human oligodendrocyte-precursor-cells (hOPCs). We engineered knock-in hESC-reporter lines in which an Identification-and-Purification tag is expressed under control of the endogenous, OPC-specific, PDGFR promoter, and performed time-course single-cell-RNA-sequencing of purified hOPCs. Our analysis uncovered marked transcriptional heterogeneity of PDGFR+ hOPCs and identified regulatory genes and networks that control their differentiation and myelination competence. Pseudotime trajectory analysis revealed two distinct trajectories for the development of oligodendrocytes vs astrocytes from hOPCs. We also identified novel transcription factors and other genes that developing hOPCs potentially use to choose between oligodendrocyte vs astrocyte lineages. In addition, pathway enrichment analysis followed by pharmacological intervention of those pathways confirm that mTOR and cholesterol biosynthesis signaling pathways are involved in maturation of oligodendrocytes from hOPCs. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.27.316133v1?rss=1 Authors: Yellajoshyula, D., Pappas, S. S., Rogers, A., Choudhury, B., Cookson, M., Reed, X., Shakkottai, V., Giger, R., Dauer, W. T. Abstract: Mechanisms controlling myelination during CNS maturation play a pivotal role in the development and refinement of CNS circuits. The transcription factor THAP1 is essential for timing the inception of myelination during CNS maturation through a cell-autonomous role in the oligodendrocyte lineage. Here, we demonstrate that THAP1 modulates ECM composition by regulating glycosaminoglycan (GAG) catabolism within oligodendrocyte progenitor cells (OPCs). Thap1-/- OPCs accumulate and secrete excess GAGs, inhibiting their maturation through an auto-inhibitory mechanism. THAP1 controls GAG metabolism by binding to and regulating the GusB gene encoding {beta}-glucuronidase, a GAG-catabolic lysosomal enzyme. Applying GAG-degrading enzymes or overexpressing {beta}-glucuronidase rescues Thap1-/- OL maturation deficits in vitro and in vivo. Our studies establish lysosomal GAG catabolism within OPCs as a critical mechanism regulating oligodendrocyte development. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.23.309682v1?rss=1 Authors: Chacon-de-la-Rocha, I., Fryatt, G., Rivera, A., Restani, L., Caleo, M., Raineteau, O., Gomez-Nicola, D., Butt, A. M. Abstract: Oligodendrocyte progenitor cells (OPCs) are responsible for generating oligodendrocytes, the myelinating cells of the CNS. Life-long myelination is promoted by neuronal activity and is essential for neural network plasticity and learning. OPCs are known to contact synapses and it is proposed that neuronal synaptic activity in turn regulates OPC proliferation and differentiation. To examine this in the adult, we performed unilateral injection of the synaptic blocker botulinum neurotoxin A (BoNT/A) into the hippocampus of adult mice. We confirm BoNT/A cleaves SNAP-25 in the CA1 are of the hippocampus, which has been proven to block neurotransmission. Notably, synaptic silencing by BoNT/A significantly decreased OPC density and caused their shrinkage, as determined by immunolabelling for the OPC marker NG2. Inhibition of synaptic activity resulted in an overall decrease in the number of OPC processes, as well as a decrease in their lengths and branching frequency. These data indicate that synaptic activity is important for maintaining adult OPC numbers and cellular integrity, which is relevant to pathological scenarios characterized by decreased synaptic activity. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.23.309666v1?rss=1 Authors: Chacon-de-la-Rocha, I., Fryatt, G., Rivera, A. D., Verkhratsky, A., Raineteau, O., Gomez-Nicola, D. M., Butt, A. M. Abstract: Myelin disruption is a feature of natural aging and of Alzheimer's disease (AD). In the CNS, myelin is produced by oligodendrocytes, which are generated throughout life by oligodendrocyte progenitor cells (OPCs). Here, we examined age-related changes in OPCs in APP/PS1 mice, a model for AD-like pathology, compared with non-transgenic (Tg) age-matched controls. Analysis was performed in the CA1 area of the hippocampus following immunolabelling for NG2 with the nuclear dye Hoescht, to identify OPC and OPC sister cells, a measure of OPC replication, together with Gpr17 and Olig2 for oligodendrocytes and myelin basic protein (MBP) immunostaining as a measure of myelination. The results indicate a decrease in the number of OPCs between 9 and 14 months in natural ageing and this occurred earlier at 9 months in APP/PS1 mice, without further decline at 14 months. The number of OPC sister cells was unaltered in natural aging, but declined significantly at 14-months in APP/PS1 mice. The number of GPR17+ and Olig2+ oligodendrocytes was not altered in APP/PS1, whereas MBP immunostaining increased between 9 and 14 months in natural ageing, but not in APP/PS1 mice. Notably, OPCs displayed marked morphological changes at 14 months in APP/PS1 mice, characterized by an overall shrinkage of OPC process domains and increased process branching, characteristic of reactive pathological changes. The results indicate that OPC and myelin disruption are pathological signs in the APP/PS1 mouse model of AD. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.10.143941v1?rss=1 Authors: Langley, M. R., Choi, C.-I., Peclat, T. R., Kleppe, L., Simon, W. L., Yoon, H., Chini, C. C., Chini, E. N., Scarisbrick, I. A. Abstract: Western-style diets cause disruptions in myelinating cells and astrocytes within the CNS. We identified increased CD38 expression in the mouse spinal cord following chronic high fat consumption or focal demyelinating injury. CD38-catalytically inactive mice are significantly protected from high fat-induced NAD+ depletion, oligodendrocyte loss, oxidative damage, and astrogliosis. 78c, a CD38 inhibitor, increased NAD+ and attenuated neuroinflammatory changes in astrocytes induced by saturated fat. Conditioned media from saturated fat-treated astrocytes impaired oligodendrocyte differentiation pointing to indirect mechanisms of oligodendrogliopathy. Combined saturated fat and lysolecithin demyelination in cerebellar slices resulted in additional deficits in myelin proteins that were mitigated by concomitant 78c treatment. Importantly, oral 78c increased counts of oligodendrocytes and remyelinated axons after focal demyelination. Our findings suggest that high fat diet impairs oligodendrocyte survival and differentiation through astrocyte-linked mechanisms mediated by the NAD+ase CD38, and highlight the use of CD38 inhibitors as potential therapeutic candidates to improve myelin regeneration. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.21.108373v1?rss=1 Authors: Foerster, S., Neumann, B., McClain, C., Di Canio, L., Chen, C., Reich, D., Simons, B. D., Franklin, R. Abstract: Oligodendrocytes that generate new myelin sheaths around demyelinated axons in the regenerative process of remyelination are generally derived from oligodendrocyte progenitor cells (OPCs). During this process, OPCs become activated, populate the area of myelin loss, and finally differentiate. Although much is known about the individual stages of remyelination, the exact sequence of events and whether a dependency of each individual stage on each other exists is unknown. Understanding the biology behind these questions is important for the development of remyelination therapies to overcome the age-related decline in remyelination efficiency observed in the chronic phase of multiple sclerosis (MS). Here we show that, following toxin-induced demyelination, all re-populating OPCs first migrate into the site of damage, undergo relatively few rounds of division and eventually differentiate. We further show that OPC proliferation is a requirement for differentiation. Together, our results reveal an unexpected link between OPC proliferation and differentiation, and opens up the possibility of novel regenerative strategies in MS focussing on stimulating OPC proliferation. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.21.108209v1?rss=1 Authors: Auderset, L., Pitman, K. A., Cullen, C. L., Pepper, R. E., Taylor, B. V., Foa, L., Young, K. M. Abstract: Low-density lipoprotein receptor-related protein 1 (LRP1) is a large, endocytic cell surface receptor that is highly expressed by oligodendrocyte progenitor cells (OPCs), and LRP1 expression is rapidly downregulated as OPCs differentiate into oligodendrocytes (OLs). We report that the conditional deletion of Lrp1 from adult mouse OPCs (Pdgfr-CreER :: Lrp1fl/fl) increases the number of new myelinating OLs added to brain, but that each new cell elaborates a normal quantity of myelin. OPC proliferation is also elevated following Lrp1 deletion in vivo, however, this is likely to be a secondary, homeostatic response to increased OPC differentiation, as our in vitro experiments show that LRP1 is a direct negative regulator of OPC differentiation, not proliferation. Deleting Lrp1 from adult OPCs also enhances remyelination, as cuprizone-induced lesions are smaller in Lrp1-deleted mice, and parenchymal OPCs produce a larger number of mature OLs. These data suggest that the selective blockade of LRP1 function on adult OPCs may enhance myelin repair in demyelinating diseases, such as multiple sclerosis. Copy rights belong to original authors. Visit the link for more info

A brief preview of the upcoming full episode. Host Kevin Patton reveals upcoming topics (therapy to grow brain cells, smelling without olfactory bulbs, flashcards on steroids) Plus word dissections and a book club recommendation (The Body —A Guide for Occupants), and more! 00:19 | Topics 02:02 | Sponsored by HAPI Online Graduate Program 02:43 | Word Dissection 13:45 | Sponsored by HAPS 14:21 | Book Club 19:06 | Sponsored by AAA 19:44 | Staying Connected If you cannot see or activate the audio player click here. Questions & Feedback: 1-833-LION-DEN (1-833-546-6336) Follow The A&P Professor on Twitter, Facebook, Blogger, Nuzzel, Tumblr, or Instagram! Upcoming Topics 2 minutes Something Smells Odd People who can smell just fine but whose MRIs show that they don't have olfactory bulbs Revisiting the topic of making new neurons in the adult human brain. Gene therapy for repairing brain injury Flashcards Their hidden powers Beyond the basics Sponsored by HAPI Online Graduate Program 0.5 minute The Master of Science in Human Anatomy & Physiology Instruction—the MS-HAPI—is a graduate program for A&P teachers. A combination of science courses (enough to qualify you to teach at the college level) and courses in contemporary instructional practice, this program helps you power up  your teaching. Kevin Patton is a faculty member in this program. Check it out! nycc.edu/hapi Word Dissection 11 minutes anosmia cribriform plate ethmoid bone polydendrocyte oligodendrocyte NG2 cell (NG2 glia) flashcard hornbook (see image my-ap.us/2YB9MMO) Sponsored by HAPS 0.5 minute The Human Anatomy & Physiology Society (HAPS) is a sponsor of this podcast.  You can help appreciate their support by clicking the link below and checking out the many resources and benefits found there. Don't forget the HAPS Awards, which provide assistance for participating in the HAPS Annual Conference. Anatomy & Physiology Society theAPprofessor.org/haps Book Club 4.5 minutes The Body – A Guide for Occupants by Bill Bryson amzn.to/2rBQNWm Recommended by Marty Port Storytelling is the Heart of Teaching A&P | Episode 12 Anatomic Variations in Humans | Fabella | Situs Inversus | Episode 43 Special opportunity Contribute YOUR book recommendation for A&P teachers! Be sure include your reasons for recommending it Any contribution used will receive a $25 gift certificate The best contribution is one that you have recorded in your own voice (or in a voicemail at 1-833-LION-DEN) Check out The A&P Professor Book Club Sponsored by AAA 0.5 minutes A searchable transcript for this episode, as well as the captioned audiogram of this episode, are sponsored by the American Association for Anatomy (AAA) at anatomy.org. Searchable transcript Captioned audiogram    If the hyperlinks here are not active, go to TAPPradio.org to find the episode page. More details at the episode page. Transcript available at the script page. Listen to any episode on your Alexa device. Need help accessing resources locked behind a paywall? Check out this advice from Episode 32 to get what you need! https://youtu.be/JU_l76JGwVw?t=440   Tools & Resources  Amazon TextExpander Rev.com Snagit & Camtasia The A&P Professor Logo Items   Sponsors   Transcript and captions for this episode are supported by the  American Association for Anatomy. anatomy.org   The Human Anatomy & Physiology Society  also provides marketing support for this podcast.  theAPprofessor.org/haps   Distribution of this episode is supported by  NYCC's online graduate program in  Human Anatomy & Physiology Instruction (HAPI)  nycc.edu/hapi   Clicking on sponsor links  helps let them know you appreciate their support of this podcast!   Follow The A&P Professor on  Twitter, Facebook, Blogger, Nuzzel, Tumblr, or Instagram!   The A&P Professor® and Lion Den® are registered trademarks of Lion Den Inc. (Kevin Patton)  

[intro music]   Host – Dan Keller Hello, happy new year, and welcome to Episode Twenty-Six of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features an interview with Tim Kennedy about remyelination and neural development. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.   According to a new clinical trial, azathioprine, or AZA, may be as effective as interferon beta. The generic immunosuppressant was effective in both reducing relapses and reducing new brain lesions in the multicenter trial. This may not be surprising since the drug has been used off-label to treat MS for several decades. If trials continue to go well, AZA may become the go-to alternative for patients who can’t afford brand name interferons.   A pair of Canadian studies recently showed that both neurodegeneration and inflammation may start in the early stages of pediatric multiple sclerosis. One team found epitope spreading in the blood of children shortly after the onset of MS, suggesting a potential new diagnostic tool. Though children comprise only 2 to 10 percent of the MS population, data gleaned from them may provide insights into the disease as a whole.   If you enjoyed our end-of-the-year interview with Alan Alda and find MSDF to be helpful, please consider supporting us with a donation. We share Mr. Alda’s philosophy that closing the gaps between scientific disciplines is key to improving scientific progress. To make a donation, visit msdiscovery.org and click on the green “Support MSDF” button next to “Research Resources”.   [transition music]   Now to the interview. Tim Kennedy is a researcher at the Montreal Neurological Institute. He met with MSDF to talk about the role of certain molecules and receptors necessary for oligodendrocyte development, maintenance, and function and their implications for remyelination.   Interviewer – Dan Keller Welcome, Dr. Kennedy. Let's talk about the life of oligodendrocytes. These are important for myelination and probably play a role in remyelination. What is the life of an oligodendrocyte? How does it start out? And what does it react to?   Interviewee – Tim Kennedy Many labs around the world have been studying the life history of an oligodendrocyte and also the lineage of the cells and how they differentiate during normal development. One of the reasons for doing this is that oligodendrocyte precursor cells are present in the mature nervous system and almost certainly contribute to remyelination in demyelinating diseases like MS. Oligodendrocyte precursors are born in the early embryonic CNS, and from the very restricted regions where they're born they then migrate away to populate all of the regions of the mature CNS where myelin occurs. In the lab here, we've been very interested in the molecular cues that direct and influence oligodendrocyte precursor migration. These include a family of proteins called netrins that we work on. And receptors for netrin like a protein called DCC. DCC stands for deleted in colorectal cancer. It was originally identified in cancer, and we now know that it has a critical role in the central nervous system in the migration, maturation, and maintenance of myelin by mature oligodendrocytes.   MSDF Some of these molecules take on different functions as the oligodendrocytes mature. How do they react, or what do these molecules do over time?   Dr. Kennedy When an oligodendrocyte precursor is born, it makes the netrin receptor DCC, but it doesn't make netrin. What the cell does is it responds to netrin in the environment, and through DCC reacts to it, and the netrin directs the cells to migrate. It tells them to initially migrate away from the position where they're born and sends them in the direction of axon tracks that require myelination. In mature myelinating oligodendrocytes, one of the huge surprises we had is that both of these proteins are made. Now, both netrin and DCC are required for normal neural development. If we examine a conventional knockout mouse that lacks either netrin-1 or DCC, those mice die within a few hours of being born, and there's a massive disorganization of the nervous system. So these are essential for normal neural development. When we look at the mature nervous system, we see that every single oligodendrocyte, every single mature myelination oligodendrocyte, makes readily detectable levels of netrin-1 and also the receptor for netrin-1, DCC. And a very simple statement of the question that we wanted to answer is what's the point of that? Why do these cells make these proteins that are essential for normal neural development but make them in the adult nervous system? In every adult human that we encounter, every single person, we're making netrin-1 and DCC in our brains right now. So what's the point? One of the functions that we've recently identified is that DCC produced by oligodendrocytes is required for the maintenance of myelin. Now what that means is that initially when we looked at the distribution of netrin-1 and DCC in relation to myelin we see that they're enriched at paranodal junctions. Paranodes are at the ends of internodes that are the regions of compact myelin that wrap and insulate an axon. The paranodes are a specialization that's made by the oligo that then connects it and ties it down to the surface of the axon. The paranodes flank the node of Ranvier, which is the key point, the specialized region along an axon that regenerates the action potential. So if we think of the internode of compact myelin as the region where the oligodendrocyte insulates the axon and allows the action potential to jump from node to node, the paranodes are the specializations at the end that tie it down. Now, the paranode is where we see the netrin and DCC enriched. If we take away either netrin-1 or DCC from oligodendrocytes, what we see is that the paranodes begin to come apart. Now in a very recent publication, what we did was use a genetic trick called cre-lox recombination to selectively take DCC out of mature myelinating oligodendrocytes. In these mice, the mice develop perfectly normally, the nervous system develops normally, the myelin develops normally. But then, at two months of age, we induce the deletion of DCC only from oligodendrocytes. Now having taken DCC out of oligodendrocytes, what we see is that first the paranodal junctions start to come apart, and then as we let the mice age the compact myelin itself starts to become disorganized. Now, that's interesting because what we're able to document in these mice is a progressive disorganization of the myelin produced by the oligodendrocyte. The progression is interesting, obviously, because we believe that this has identified a new mechanism that maintains myelin, and we would then relate that to the progression of demyelinating disorders like multiple sclerosis. A consequence of having lost DCC is that the action potential conduction velocity in the nervous system is delayed, and when we look at the mice themselves – and look at their behavior, put them through behavioral tests – what we see is that they become uncoordinated and slower in their movements. So again, this would all be consistent with this disruption of the myelin along the axons in the central nervous system due to the loss of DCC. And it's an indication that DCC being made by oligodendrocytes is absolutely essential to maintain the appropriate organization of myelin.   MSDF That explains why myelin may become disorganized. Now, if there is a state in which it's already disorganized, which we look at someone with MS, is there any indication here how to remyelinate knowing what you now know about what's required for maintenance of myelin?   Dr. Kennedy Certainly. What's really exciting having found that DCC is essential to maintain myelin is that this is a new biochemical mechanism that is required to organize and maintain the structural paranodal junctions, and that that's critical for the integrity and the maintenance of compact myelin. Now, DCC is a transmembrane receptor, and every single component of the signal transduction pathway downstream of DCC is potentially a drug target that could be manipulated to enhance the maintenance of myelin. So this is a new biochemical mechanism that exists in oligodendrocytes that promotes myelin maintenance. And that has enormous potential for trying to encourage the persistence of myelin in demyelinating disease.   MSDF What about remyelination? I think you've said oligodendrocytes are born to myelinate. What's stopping them?   Dr. Kennedy If we go back to the oligodendrocyte precursor in early development, what our studies of the developing nervous demonstrated was that oligodendrocyte precursors are repelled by netrin-1. The normal function of netrin-1 in the early embryo is to drive oligodendrocyte precursors away from where they're born so that they can go out into the rest of the central nervous system, find axons that need to be myelinated and myelinate them. That indicates that in the early embryo netrin-1 is a repellent for these cells. Again, we recently reported that in human MS plaques netrin-1 is present in those plaques. Where that's likely coming from is from the wreckage of cells that have died in those plaques. So I had said that mature myelinating oligodendrocytes express netrin-1. When those cells die and when the myelin is lost, the debris from those cells remains behind and potentially even builds up in plaques. There are a number of inhibitors of oligodendrocyte precursor migration that we now know are present in human MS plaques. These include proteins like chondroitin sulfate proteoglycans, semaphorins, and now netrin. What that strongly suggests is that when oligodendrocyte precursors are migrating in the adult brain to sites of demyelination with the intention of remyelinating an axon that has been demyelinated these inhibitors will very likely prevent those cells from entering the plaque and doing what they were born to do, which is to remyelinate. A very exciting thing about MS research today is that we know that the brain contains stem cells that produce oligodendrocyte precursor cells that readily give birth to these cells. So all of us have oligodendrocyte precursor cells in our head. Those cells are born to myelinate. They will migrate towards plaques where demyelination has happened, and if they're allowed to enter the plaque find the axon that needs to be remyelinated. And if they can be encouraged to overcome whatever it is that is blocking them from remyelinating, potentially that aspect of MS remyelination could be encouraged to happen.   MSDF Do you have some ideas on how to overcome this blockage either clearing away the debris or making the oligodendrocytes insensitive to the inhibitors and the debris?   Dr. Kennedy Both of those approaches would be very appropriate. So encouraging the nervous system to clear away the debris we would predict that that would encourage remyelination to happen. In addition, although I said there were multiple inhibitors present in MS plaques – and those inhibitors have different receptors – downstream of those receptors it's very likely that common signal transduction mechanisms are engaged. So targeting those common signal transduction mechanisms inside the migrating oligodendrocyte precursor cell could very potentially nullify all of the inhibitors at once. If it was possible to turn off the sensitivity to those inhibitors, then we would predict that the cells would enter the plaque more readily, and more of the cells would then be able to encounter the axons that require remyelination, and we would obviously predict that that would promote remyelination happening.   MSDF What are some of the big questions now to look at, solve?   Dr. Kennedy The oligodendrocyte is an absolutely fascinating cell type. It's a highly specialized cell type, critically clinically important. We still understand very little about these cells. The mechanisms that I've been talking about that regulate the maintenance of myelin, those have only very recently been discovered. And I think it's extremely exciting that this type of thing is being found in oligodendrocytes. But these are still very mysterious cell types. I think the more we understand about the cell biology of the oligo the more we'll be able to target pathways in the biochemistry of oligodendrocytes to try and promote things like myelin maintenance and the ability to remyelinate. Being able to do those things and essentially manipulate these cells in specific ways, we can then overcome specific clinical issues.   MSDF Does this go beyond MS? Are there other conditions that it applies to?   Dr. Kennedy I think there are two things built into that question. One is that there are many diseases for which the cause either isn't clear – and MS would be in that category – or there are also diseases that have many different causes, but they may manifest in similar ways. So by understanding oligodendrocytes and being able to encourage oligodendrocytes to remyelinate, that could have broad applicability for treating the symptoms of many different forms of demyelinating disease irrespective of the cause of those diseases. Beyond that, as we come to better understand how cells move in the nervous system, how they migrate, how they form attachments, how they connect to each other, and how they maintain those connections, those kinds of insights are going to have broad applicability for all sorts of neurodegenerative diseases where the basic problem in the neurodegenerative disease is that the networks that are the nervous system are coming apart. And if we can encourage those networks to just stay together or rebuild themselves, then I think that again has broad applicability to many types of neurodegenerative diseases in the myelinating field and outside of myelination, as well.   MSDF It sounds like it may even have applicability to not only neurodegeneration but in development where you may have miswiring such as potentially an autism or something like that.   Dr. Kennedy Yeah. An exciting thing is that a lot of the mechanisms that I'm thinking about and we're thinking about in the lab is that the insights that got us working on myelin, that brought us to work on myelin really came from neural development and better understanding neural development; the studies of neural development identified proteins and gene families that have very, very potent actions in the nervous system. When we then looked at expression, we saw that they were expressed in the mature CNS, and that brought forth a whole other group of questions related to the function of the normal adult nervous system and also the degeneration of the adult nervous system in neurodegenerative disease. The exciting thing about that is that as we understand the molecular biology of the central nervous system better that's going to be applicable to development, to normal function, to enhanced function, and also promoting function in degenerative conditions.   MSDF I appreciate it. Thank you.   Dr. Kennedy You're very welcome.   [transition music]   Thank you for listening to Episode Twenty-Five of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.   Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.   We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.   [outro music]          

Myelin Oligodendrocyte Glycoprotein (MOG) is one of the few proteins known to be localized on the outermost sheath of central nervous system (CNS) myelin. Due to this localization, MOG is accessible to antibodies. Anti-MOG antibodies are demyelinating and enhance clinical symptoms in a number of animal models of CNS inflammation. Autoantibodies recognizing conformationally intact MOG are found in different inflammatory diseases of the CNS, but their antigenic epitopes had not been mapped. In this work, 9 variants of MOG with an intracellular enhanced green fluorescent protein (EGFP) tag were expressed on the cell surface of human HeLa cells and used to analyze sera from 111 patients (104 children, 7 adults), who had antibodies recognizing cell-bound human MOG. These patients had different diseases, namely acute disseminated encephalomyelitis (ADEM), one episode of transverse myelitis or optic neuritis, multiple sclerosis (MS), anti-aquaporin-4 (AQP4)–negative neuromyelitis optica (NMO), and chronic relapsing inflammatory optic neuritis (CRION). The expression levels of the mutants were comparable and cells with a defined expression level (fluorescence intensity in the EGFP channel of 102-103) were gated. Each MOG-mutant was recognized by at least one MOG-specific mAb. This allowed the comparison of binding to the different mutants. In order to assess the reproducibility of the system, binding of the 111 sera to the mutants was analyzed up to three times in independent experiments, yielding a very good reproducibility of the binding percentage with an absolute SD of 7.8% in the case of low recognition of a mutant and a relative SD of 20% in the case of high recognition of a mutant. The applied variants of MOG gave insight into epitope recognition of 98 patients. All epitopes identified in this work were located at loops connecting the ß-strands of MOG. The immunodominant epitope of human anti-MOG antibodies was at the membrane-proximal CC’-loop containing aa42, which is not present in rodent MOG. This loop was recognized by about half of all patients. Overall, seven epitope patterns were distinguished, including the one mainly recognized by mouse mAbs at the FG-loop around aa104. Evidence from mouse models of CNS inflammation shows that anti-MOG antibodies recognizing different epitopes can be demyelinating and thus pathogenic. This suggests that not only those antibodies recognizing the same epitope of MOG as the pathogenic mAbs (i.e. the FG-loop), but also the ones recognizing the CC'-loop are pathogenic in humans, as both epitopes allow for the recognition of cell-bound MOG. In half of the patients, the anti-MOG response was directed to a single epitope. To analyze the effect of glycosylation on the recognition of MOG by human autoantibodies, a “non-glycosylation mutant” N31D was made. Digestion with PNGaseF and Western blot analysis confirmed that N31 was the only used N-glycosylation site of the MOG constructs in HeLa cells. Glycosylation of MOG was not needed for antibody binding, but 8% of the patients recognized deglycosylated MOG at least two-fold better. The epitope specificity was not linked to certain disease entities. The individual epitope recognition patterns stayed constant in 11 analyzed patients over an observation period of up to 5 years without evidence for intramolecular epitope spreading. Some patients with acute syndromes had anti-MOG IgG at disease onset, but rapidly lost their anti-MOG IgG reactivity. These patients were able to generate a long-lasting IgG response to measles and rubella virus vaccine indicating that the loss of anti-MOG reactivity was not reflective of a lack of capacity for longstanding IgG responses. Human anti-MOG antibodies are mainly of the IgG1 isotype, which can activate complement and antibody dependent cellular cytotoxicity. Upon binding to MOG in the CNS, human anti-MOG antibodies are hence expected to cause demyelination. Transfer experiments with purified human anti-MOG antibodies have not been performed yet. The fact that the majority of human anti-MOG antibodies did not recognize rodent MOG has implications for animal studies. Using the described assay will help to identify patient samples appropriate for these transfer experiments and finally lead to the formal proof of the pathogenicity of human anti-MOG antibodies. This work also gives important information for future detection of potential mimotopes and the development of anti-MOG antibody detection assays and might pave the way to antigen-specific depletion.

Listen to Bridget Shafit-Zagardo discuss her latest ASN NEURO paper on how Gas6 enhances axonal ensheathment by MBP+ membranous processes in human DRG/OL promyelinating co-cultures.

Multiple system atrophy is a parkinsonian neurodegenerative disorder. It is cytopathologically characterized by accumulation of the protein p25α in cell bodies of oligodendrocytes followed by accumulation of aggregated α-synuclein in so-called glial cytoplasmic inclusions. p25α is a stimulator of α-synuclein aggregation, and coexpression of α-synuclein and p25α in the oligodendroglial OLN-t40-AS cell line causes α-synuclein aggregate-dependent toxicity. In this study, we investigated whether the FAS system is involved in α-synuclein aggregate dependent degeneration in oligodendrocytes and may play a role in multiple system atrophy. Using rat oligodendroglial OLN-t40-AS cells we demonstrate that the cytotoxicity caused by coexpressing α-synuclein and p25α relies on stimulation of the death domain receptor FAS and caspase-8 activation. Using primary oligodendrocytes derived from PLP-α-synuclein transgenic mice we demonstrate that they exist in a sensitized state expressing pro-apoptotic FAS receptor, which makes them sensitive to FAS ligand-mediated apoptosis. Immunoblot analysis shows an increase in FAS in brain extracts from multiple system atrophy cases. Immunohistochemical analysis demonstrated enhanced FAS expression in multiple system atrophy brains notably in oligodendrocytes harboring the earliest stages of glial cytoplasmic inclusion formation. Oligodendroglial FAS expression is an early hallmark of oligodendroglial pathology in multiple system atrophy that mechanistically may be coupled to α-synuclein dependent degeneration and thus represent a potential target for protective intervention.

Klaus Nave PhD, Director of the Max Planck Institute of Experimental Medicine, discusses the emerging role of oligodendrocytes in ALS and potential treatment strategies going forward. Read more: http://blogs.als.net/post/2012/10/29/ALS-dressed-to-the-C9s.aspx

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) accompanied by demyelination and axonal loss. Only a minority of the demyelinated MS lesions gets remyelinated. In animal models, however, remyelination is the default program following immune-mediated or toxic demyelination. This thesis aims to find factors regulating remyelination in MS. The starting point was autoptic tissue from MS patients. First, different types of MS lesions were macrodissected namely, chronic inactive demyelinated lesions that had failed to remyelinate, lesions undergoing active demyelination and remyelinated lesions. Healthy white matter was used as control tissue. Gene expression profiles of these lesions were established using quantitative PCR low density arrays. Thereby the focus was on the extracellular matrix (ECM) and on factors known to regulate the biology of oligodendrocytes. ECM components can regulate oligodendrocyte differentiation and modify immune reactions in multiple ways, e.g., by sequestering or displaying growth factors and by directly interacting with immune cells and glial cells. The expression of 50 ECM components and 34 ECM degrading enzymes was measured by qPCR. COL1A1, COL3A1, COL5A1 and COL5A2 chains were strongly induced in active lesions and even more in chronic inactive lesions. These collagen polypeptide chains interact to form collagen types I, III and V, which are grouped as fibrillar collagens. Furthermore, two Small Leucine Rich Proteoglycans (SLRPs), biglycan and decorin, which can decorate fibrillar collagens, were also strongly induced. Immunostaining localized the fibrillar collagens, biglycan, and decorin around blood vessels. These ECM molecules were largely seen in the perivascular space closely associated with infiltrating immune cells forming a mesh between the endothelium and the astrocytic glia limitans. In active lesions collagen V was also seen in the heavily infiltrated brain parenchyma. Since these ECM molecules were found largely in the perivascular space close to immune cells and hardly in the surrounding parenchyma where oligodendrocyte differentiation takes place, the interaction of these ECM components with immune cells was further analysed. In vitro experiments revealed that the fibrillar collagens I and III inhibited the monocytic production of CCL2 (MCP-1), an inflammatory chemokine thought to be involved in the recruitment of immune cells to the inflamed brain. This suggests that the induced fibrillar collagens may contribute to the limitation of MS lesions expansion by inhibition of the CCL2 production by monocytes. The second set of analysed genes comprised 32 factors regulating survival, proliferation and/or differentiation of oligodendrocytes and 18 receptors of these genes. The key factors for oligodendrocyte differentiation (IGF1, IGF2 and CNTF) and oligodendrocyte proliferation (FGF2 and PDGFAA) were still present in demyelinated lesions, although their expression ratio was altered. The most striking result was the up-regulation of FGF9 in a subset of chronically demyelinated lesions, but in none of the remyelinated shadow plaques. The potential functional role of this observation was investigated by treating myelinating rat central nervous system cultures with exogenous FGF9. In this experimental setting, FGF9 inhibited the ability of mature oligodendrocytes to myelinate and ensheath axons. All these data suggests that the induction of FGF9 in some chronic MS lesions is one of the inhibitory mechanisms accounting for the failure of remyelination. Together, this thesis has two main findings: A) Fibrillar collagens, biglycan and decorin form a perivascular fibrosis and the fibrillar collagens I and III inhibit production of CCL2 by monocytes. Inhibition of CCL2 production by fibrillar collagens might contribute to lesion confinement. B) Expression profiles of remyelinated MS lesions were established for the first time and thereby, up-regulation of FGF9 in demyelinated, but not in remyelinated lesions was revealed. The inhibition of myelination in vitro by FGF9 suggests that this is one potential mechanism to explain why demyelinated lesions expressing higher FGF9 level fail to remyelinate.

Some glial cells can generate action potentials and are hypersensitive to ischemic injury.

This study investigated the immunobiology of MOG-induced EAE in the DA rat, an animal model, which reproduces the immunopathology of the type II MS lesion (Lucchinetti et al., 2000). A newly established immunisation protocol results in a highly synchronised biphasic form of EAE, which mimics the disease course of secondary progressive MS, albeit in a strongly abbreviated time course (Figure 3.1.1). This study demonstrates that MOG-specific autoantibodies are responsible for initiating clinical relapse and driving disease progression. On the background of mild, sub-clinical inflammatory activity in the CNS, pathogenic antibodies enter the CNS and mediate demyelination, a process that in turn amplifies the local inflammatory response (Figure 3.1.14 A). It should however be noted that lethal clinical relapses may also occur in the absence of a pathogenic antibody response if an inflammatory lesion develops in a region of the CNS that is particularly sensitive to damage, or where it may perturb vital functions, such as the brain stem. Although antibodies have been shown to amplify the severity of ongoing clinical EAE (Schluesener et al., 1987; Linington et al., 1988; Lassmann et al., 1988), firm evidence for a role in driving relapse and disease progression was missing. This study has now established this principal, which in all probability is relevant to our understanding of the pathogenesis of severe, steroid non-responsive relapses in MS patients. However, this model of EAE is an artificial system, in which the role of antibody is only apparent because of the different kinetics of MOG-specific T and B cell responses. In MS we still have to answer two crucial questions, namely the identity of the autoantigens targeted by the demyelinating antibody response, and the factors that may trigger this response. MOG is the only myelin protein known to initiate a demyelinating antibody response in EAE, and MOG-induced EAE has provided a valuable tool to identify the role of pathogenic autoantibodies in immune mediated demyelination. However, there is a major discrepancy between the proportion of MS patients with pathogenic MOG-specific antibodies in their circulation (5%; Haase et al., 2000) and the frequency of patients with pathological changes suggestive of antibody-mediated pathomechanisms (>50%; Lucchinetti et al., 2000). This discrepancy may in part be accounted for by the absorption of the pathogenic antibodies into the CNS, which will lead to a dramatic reduction of the antibody titre in the periphery, as demonstrated in section 3.1.3.4 of this study. On the other hand, it is unlikely that MOG is the only target autoantigen, which is exposed on the myelin surface and can therefore initiate a demyelinating autoantibody response. The identification of potential targets is a prerequisite to develop diagnostic kits to identify those patients with pathogenic autoantibody responses and then provide an appropriate therapy such as plasma exchange, or immuno-absorption. As demonstrated in this study, DNA vaccination using a plasmid encoding a myelin antigen is one approach to generate high titre autoantibody responses directed against the native protein. The pathogenicity of this antibody response can then be assayed in the same animal by inducing EAE. This method circumvents problems such as purity, yield and denaturation, all of which complicate any study using antigens isolated from the CNS or generated using recombinant technologies. Coupling this approach to a proteomics based analysis of the myelin membrane and reverse genomics to identify candidate gene products provides the means to map out those protein antigens that can be targeted by a demyelinating autoantibody response. The feasibility of this concept is currently being tested in the rat using PLP and MAG as myelin components that may in certain circumstances provoke a pathogenic autoantibody response. Such an analysis will, however, not detect pathogenic antibody responses to glycolipid antigens, which are major target autoantigens in a number of diseases affecting the peripheral nervous system such as Guillain Barré syndrome (GBS). In GBS a pathogenic antibody response to gangliosides appears to be triggered by infections with particular serotypes of Campylobacter jejuni (Fredman, 1998; Willison and O´Hanlon, 1999). In the majority of patients these antibody responses are an acute phenomenon and disappear as the patients recover (Hahn, 1998). It is conceivable that a similar mechanism is responsible for the initiation of severe relapses in some MS patients, if an infection triggers a cross-reactive antibody response to a surface glycolipid epitope. This would induce an episode of acute CNS demyelination that would not be immediately responsive to immunosuppressive therapy, as tissue damage and amplification of the local inflammatory response would be driven by the pre- existing antibody response. Analysis of the autoantibody responses in MS should therefore be extended to examine lipid as well as protein autoantigens. Such studies should also not be restricted to myelin, but also address the question of responses to other structures such as the axon and oligodendrocyte progenitor cells. Such autoantibody responses are however only conditionally pathogenic, in other words their pathogenic potential is only expressed if they can enter the CNS across the blood brain barrier (BBB)(Litzenburger et al., 1998; Bourquin et al., 2000). In EAE the inflammatory insult to the CNS is responsible for the disruption of BBB function and the entry of antibody into the nervous system. MS is characterised by repeated episodes of CNS inflammation but what initiates and maintains this response is unclear. The observation, that DA rats develop a similar, although eventually self-limiting response in the CNS after immunisation with MOG-peptide in CFA provides a model to investigate the immuno-regulatory deficit(s) responsible for chronic CNS inflammation. The disease model is very reproducible with >90% of animals relapsing after peptide immunisation as opposed to