Podcasts about als ftd

In this episode we discuss research on patient and family experiences in neurogenetics. You can find the Journal of Genetic Counseling webpage via onlinelibrary.wiley.com or via the National Society of Genetic Counselors website.    Segment 1: “Individuals' experiences in genetic counseling and predictive testing for familial amyotrophic lateral sclerosis” Connolly Steigerwald is a certified genetic counselor at NYU Langone Health's Division of Neurogenetics and Lysosomal Storage Disorders Program in NYC, where she assists in providing evaluations and genetic counseling for those with suspected or confirmed neurogenetic disorders. Her clinic population includes those with neurodevelopmental disabilities, epilepsies, neuromuscular disorders, dementias, white matter disorders, movement disorders, and lysosomal storage disorders. Connolly holds a Master of Science in Genetic Counseling from Columbia University, where she completed a specialty rotation in neurology with a focus on neurodegenerative and neuromuscular disorders such as amyotrophic lateral sclerosis. Her research interests include predictive genetic testing, lysosomal storage disorders, and implementation of genetic counselor led clinic models. Elizabeth Harrington, MS, CGC, is an ABGC board-certified genetic counselor and Lecturer in the department of Neurology at Columbia University. Ms. Harrington received her graduate degree in human genetics and genetic counseling from the Stanford University School of Medicine.  Ms. Harrington provides genetic counseling expertise in neuromuscular, neurodegenerative, and motor neuron diseases, and specifically provides clinical genetic counseling to patients and families with ALS. In addition to her clinical and academic responsibilities, Ms. Harrington directs the ALS Families Project research study, a presymptomatic natural history study designed to understand the genetic underpinnings of genetic forms of ALS and the impact on affected families. Link to the ALS Families Project: https://clinicaltrials.gov/study/NCT03865420 In this segment we discuss: How the experiences and decision-making processes for ALS risk compare to other neurodegenerative disorders, such as Huntington disease (HD). What influences individuals at risk for familial ALS/FTD to choose predictive genetic testing, including factors like religious affiliation. The psychological impact of testing positive for ALS-associated mutations is compared to those who test negative or opt out of testing, revealing significant emotional differences. Social support networks, whether from family, friends, or healthcare professionals, are critical for those processing genetic test results or managing their risk for ALS/FTD. The importance of integrating psychological care into the predictive genetic testing process to support individuals facing the risk of neurodegenerative diseases. Segment 2: “How parents of children with ataxia-telangiectasia use dynamic coping to navigate cyclical uncertainty” Victoria Suslovitch (Tori) is a genetic counselor and works as a genomic science liaison for the rare disease team at Ambry Genetics. She educates healthcare providers about genetic testing and genomic medicine, and aims to advance access, equity, and quality of genetics services. Prior, Victoria was a research genetic counselor at Boston Children's Hospital, for a study that develops genomically targeted therapies for children with rare neurological diseases. In this role, she worked closely with families of patients with ataxia telangiectasia. She received her Master of Science in Genetic Counseling degree from Boston University, and is certified by the American Board of Genetic Counseling.  Julia Schiller works as a cancer genetic counselor at AdventHealth in Parker, CO. She attended Drake University for her undergraduate degree, and Boston University School of Medicine for her genetic counseling degree and is certified by the American Board of Genetic Counseling. Originally from Minnesota, she now enjoys all the outdoor adventures Colorado has to offer with her partner, Adam, and their dog, Sprocket. Her passionate for health equity and preventative care drive her to create a space for patients where they feel empowered in their own healthcare. Link to the Ataxia Telangiectasia Children's Project (ATCP): https://atcp.org In this segment we discuss: Ataxia-Telangiectasia (A-T) - a pediatric movement disorder characterized by ataxia, immune deficiencies, and a higher risk of cancer, with symptoms often starting in early childhood. The similarities and differences in parental experiences as well as emotional and clinical challenges faced by families The five key themes that emerged: changes in parental responsibilities, shifts in family identity, evolving coping strategies, continuous uncertainty, and the importance of support from various sources. A-T's progressive nature meant that coping and identity changes were ongoing, with parents turning to connections with family, medical teams, and other A-T families. Parents described emotional, logistical, and financial challenges associated with the diagnosis, highlighting the need for supportive and understanding healthcare providers.   Stay tuned for the next new episode of DNA Dialogues! In the meantime, listen to all our episodes Apple Podcasts, Spotify, streaming on the website, or any other podcast player by searching, “DNA Dialogues”.    For more information about this episode visit dnadialogues.podbean.com, where you can also stream all episodes of the show. Check out the Journal of Genetic Counseling here for articles featured in this episode and others.    Any questions, episode ideas, guest pitches, or comments can be sent into DNADialoguesPodcast@gmail.com.    DNA Dialogues' team includes Jehannine Austin, Naomi Wagner, Khalida Liaquat, Kate Wilson, and DNA Today's Kira Dineen. Our logo was designed by Ashlyn Enokian. Our current intern is Sydney Arlen.

Dr. Gordon Smith talks with Laynie Dratch about integrating genetic testing into patient care for persons with Amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) spectrum disorders. Read the related article in Neurology: Clinical Practice Show references: https://www.neurology.org/media/podcast/incorporating-genetic-testing-into-care-patients-als-ftd

Dr. Gordon Smith talks with Laynie Dratch about integrating genetic testing into patient care for persons with Amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) spectrum disorders.

During some of our most difficult moments, genetic counselors can help us make critical decisions about our health and the future of our family members.  Join Jennifer Reid, MD as she learns all about genetic counseling from Laynie Dratch, ScM, Certified Genetic counselor.  Discussed in this Episode:1) How does the "counseling" part of genetic counseling work?2) Why is Laynie so concerned about the increase in direct-to-consumer genetics testing like 23 and Me?3) How does she help individuals through the identity challenges when they learn about genetic risks?4) What gives her hope in the field of neurological genetics?References from EpisodeAmbiguous Loss with Pauline Boss, Ph.D. https://www.ambiguousloss.com/Jehannine C. Austin on Polygenic Risks in Psychiatric Disorders https://medgen.med.ubc.ca/jehannine-austin/Penn Frontotemporal Dementia Center https://pennftdcenter.wordpress.com/Laynie Dratch, ScM CGC is a board-certified genetic counselor for the Penn Frontotemporal Degeneration (FTD) Center and Penn Amyotrophic Lateral Sclerosis (ALS) Center in the Department of Neurology at the University of Pennsylvania. Her research interests include the lived experiences of individuals at risk of developing ALS/FTD spectrum disorders, and genetic counseling access and service delivery. Laynie completed her master's in genetic counseling at the Johns Hopkins University / National Institutes of Health genetic counseling training program and completed her undergraduate studies at Colgate University where she graduated summa cum laude with a BA in neuroscience and a minor in psychology.Jennifer Reid, MD: thereflectivedoc.comSeeking a mental health provider? Try Psychology TodayNational Suicide Prevention Lifeline: 1-800-273-8255SAMHSA's National Helpline - 1-800-662-HELP (4357)Dial 988 for Mental Health EmergencyThoughts and opinions expressed on show are those of host and guests, and not associated with any academic institution.Disclaimer:The information and other content provided on this podcast or in any linked materials, are not intended and should not be construed as medical advice, nor is the information a substitute for professional medical expertise or treatment. All content, including text, graphics, images and information, contained on or available through this website is for general information purposes only.If you or any other person has a medical concern, you should consult with your health care provider or seek other professional medical treatment. Never disregard professional medical advice or delay in seeking it because of something that have read on this website, blog or in any linked materials. If you think you may have a medical emergency, call your doctor or emergency services (911) immediately. You can also access the National Suicide Help Line at 1-800-273-8255The Reflective DocWebsite - Instagram - Facebook - Linked In - Twitter - Think Like a Shrink Blog on Psychology Today

Dr. Gordon Smith talks with Laynie Dratch about integrating genetic testing into patient care for persons with Amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) spectrum disorders. Read the related article in Neurology: Clinical Practice.  Disclosures can be found at Neurology.org 

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.17.549377v1?rss=1 Authors: Broce, I., Sirkis, D., Nillo, R. M., Bonham, L. W., Lee, S. E., Miller, B. L., Sturm, V., Sugrue, L. S., Desikan, R., Yokoyama, J. S. Abstract: Introduction: A hexanucleotide repeat expansion (HRE) intronic to chromosome 9 open reading frame 72 (C9orf72) is recognized as the most common genetic cause of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and ALS-FTD. Identifying genes that show similar regional co-expression patterns to C9orf72 may help identify novel gene targets and biological mechanisms that mediate selective vulnerability to ALS and FTD pathogenesis. Methods: We leveraged mRNA expression data in healthy brain from the Allen Human Brain Atlas to evaluate C9orf72 co-expression patterns. To do this, we correlated average C9orf72 expression values in 51 regions across different anatomical divisions (cortex, subcortex, cerebellum) with average gene expression values for 15,633 protein-coding genes, including 50 genes known to be associated with ALS, FTD, or ALS-FTD. We then evaluated whether the identified C9orf72 co-expressed genes correlated with patterns of cortical thickness in symptomatic C9orf72 pathogenic HRE carriers (n=19). Lastly, we explored whether genes with significant C9orf72 radiogenomic correlations (i.e., 'C9orf72 gene network') were enriched in specific cell populations in the brain and enriched for specific biological and molecular pathways. Results: A total of 1,748 genes showed an anatomical distribution of gene expression in the brain similar to C9orf72 and significantly correlated with patterns of cortical thickness in C9orf72 HRE carriers. This C9orf72 gene network was differentially expressed in cell populations previously implicated in ALS and FTD, including layer 5b cells, cholinergic motor neurons in the spinal cord, and medium spiny neurons of the striatum, and was enriched for biological and molecular pathways associated with multiple neurotransmitter systems, protein ubiquitination, autophagy, and MAPK signaling, among others. Conclusions: Considered together, we identified a network of C9orf72-associated genes that may influence selective regional and cell-type-specific vulnerabilities in ALS/FTD. 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/2023.07.17.549331v1?rss=1 Authors: Milioto, C., Carcole, M., Giblin, A., Coneys, R., Attrebi, O., Ahmed, M., Harris, S. S., Lee, B. I., Yang, M., Nirujogi, R. S., Biggs, D., Salomonsson, S., Zanovello, M., De Oliveira, P., Katona, E., Glaria, I., Mikheenko, A., Geary, B., Udine, E., Vaizoglu, D., Rademakers, R., van Blitterswijk, M., Devoy, A., Hong, S., Partridge, L., Fratta, P., Alessi, D., Davies, B., Busche, M. A., Greensmith, L., Fisher, E. M., Isaacs, A. M. Abstract: A GGGGCC repeat expansion in C9orf72 is the most common genetic cause of ALS and FTD (C9ALS/FTD). The presence of dipeptide repeat (DPR) proteins, generated by translation of the expanded repeat, is a major pathogenic feature of C9ALS/FTD pathology, but their most relevant effects in a physiological context are not known. Here, we generated C9orf72 DPR knock-in mouse models characterised by physiological expression of 400 codon-optimised polyGR or polyPR repeats, and heterozygous C9orf72 reduction. (GR)400 and (PR)400 knock-in mice exhibit cortical neuronal hyperexcitability, age-dependent spinal motor neuron loss and progressive motor dysfunction, showing that they recapitulate key features of C9FTD/ALS. Quantitative proteomics revealed an increase in extracellular matrix (ECM) proteins in (GR)400 and (PR)400 spinal cord, with the collagen COL6A1 the most increased protein. This signature of increased ECM proteins was also present in C9ALS patient iPSC-motor neurons indicating it is a conserved feature of C9ALS/FTD. TGF-{beta}1 was one of the top predicted regulators of this ECM signature and polyGR expression in human iPSC-neurons was sufficient to induce TGF-{beta}1 followed by COL6A1, indicating TGF-{beta}1 is one driver of the ECM signature. Knockdown of the TGF-{beta}1 or COL6A1 orthologue in Drosophila dramatically and specifically exacerbated neurodegeneration in polyGR flies, showing that TGF-{beta}1 and COL6A1 protect against polyGR toxicity. Altogether, our physiological C9orf72 DPR knock-in mice have revealed a neuroprotective and conserved ECM signature in C9FTD/ALS. 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/2023.06.26.546581v1?rss=1 Authors: Rothstein, J. D., Baskerville, V., Rapuri, S., Mehlhop, E., Jafar-nejad, P., Rigo, F., Bennett, F., Mizielinska, S., Isaacs, A., Coyne, A. N. Abstract: The G4C2 repeat expansion in the C9orf72 gene is the most common genetic cause of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Many studies suggest that dipeptide repeat proteins produced from this repeat are toxic, yet, the contribution of repeat RNA toxicity is under investigated and even less is known regarding the pathogenicity of antisense repeat RNA. Recently, two clinical trials targeting G4C2 (sense) repeat RNA via antisense oligonucleotide failed despite a robust decrease in sense encoded dipeptide repeat proteins demonstrating target engagement. Here, in this brief report, we show that G2C4 antisense, but not G4C2 sense, repeat RNA is sufficient to induce TDP-43 dysfunction in induced pluripotent stem cell (iPSC) derived neurons (iPSNs). Unexpectedly, only G2C4, but not G4C2 sense strand targeting, ASOs mitigate deficits in TDP-43 function in authentic C9orf72 ALS/FTD patient iPSNs. Collectively, our data suggest that the G2C4 antisense repeat RNA may be an important therapeutic target and provide insights into a possible explanation for the recent G4C2 ASO clinical trial failure. 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/2023.02.10.527924v1?rss=1 Authors: Nementzik, L. R., Thumbadoo, K. M., Murray, H. C., Gordon, D., Yang, S., Blair, I. P., Turner, C., Faull, R. L., Curtis, M. A., McLean, C., Nicholson, G. A., Swanson, M. E., Scotter, E. L. Abstract: Mutations in the UBQLN2 gene cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The neuropathology of such UBQLN2-linked cases of ALS/FTD is characterised by aggregates of the ubiquilin 2 protein in addition to aggregates of the transactive response DNA-binding protein of 43 kDa (TDP-43). ALS and FTD without UBQLN2 mutations are also characterised by TDP-43 aggregates, that may or may not colocalise with wildtype ubiquilin 2. Despite this, the relative contributions of TDP-43 and ubiquilin 2 to disease pathogenesis remain largely under-characterised, as does their relative deposition as aggregates across the central nervous system (CNS). Here we conducted multiplex immunohistochemistry of three UBQLN2 p.T487I-linked ALS/FTD cases, three non-UBQLN2-linked (sporadic) ALS cases, and eight non-neurodegenerative disease controls, covering 40 CNS regions. We then quantified ubiquilin 2 aggregates, TDP-43 aggregates, and aggregates containing both proteins in regions of interest to determine how UBQLN2-linked and non-UBQLN2-linked proteinopathy differ. We find that ubiquilin 2 aggregates that are negative for TDP-43 are predominantly small and punctate, and are abundant in the hippocampal formation, spinal cord, all tested regions of neocortex, medulla, and substantia nigra in UBQLN2-linked ALS/FTD but not sporadic ALS. Curiously, the striatum harboured small punctate ubiquilin 2 aggregates in all cases examined, while large diffuse striatal ubiquilin 2 aggregates were specific to UBQLN2-linked ALS/FTD. While ubiquilin 2 deposition in frontotemporal regions may enhance cognitive risk in UBQLN2-linked cases, ubiquilin 2 is deposited mainly in clinically unaffected regions throughout the CNS such that overall symptomology in these cases maps best to the aggregation of TDP-43. 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/2023.02.03.527079v1?rss=1 Authors: Cao, M. C., Ryan, B., Wu, J., Curtis, M. A., Faull, R. L., Dragunow, M., Scotter, E. L. Abstract: TDP-43 dysfunction is a molecular hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A major hypothesis of TDP-43 dysfunction in disease is the loss of normal nuclear function, resulting in impaired RNA regulation and the emergence of cryptic exons. Cryptic exons and exon changes are emerging as promising markers of lost TDP-43 function in addition to revealing biological pathways involved in neurodegeneration in ALS/FTD. Here, we investigated TDP-43 loss of function by depleting TARDBP from human post-mortem brain pericytes and identifying differential exon usage events with RNA-sequencing analysis. Differential exon usage events validated by qPCR were compiled into a panel with other well-established TDP-43 loss-of-function exon markers and then tested in ALS and control motor cortex tissue. We find that profiles of TDP-43-related cryptic exons and changed exon usage discriminate ALS brain tissue from controls, and propose that splicing panels may have predictive value for therapeutic intervention. 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/2023.01.12.523820v1?rss=1 Authors: Wang, H.-L. V., Veire, A. M., Gendron, T. F., Gearing, M., Glass, J. D., Jin, P., Corces, V. G., McEachin, Z. T. Abstract: Repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis and familial frontotemporal dementia (ALS/FTD). To identify molecular defects that take place in the dorsolateral frontal cortex of patients with C9orf72 ALS/FTD, we compared healthy controls with C9orf72 ALS/FTD donor samples staged based on the levels of cortical phosphorylated TAR DNA binding protein (pTDP-43), a neuropathological hallmark of disease progression. We identified distinct molecular changes in different cell types that take place during disease progression. These alterations include downregulation of nuclear and mitochondrial ribosomal protein genes in early disease stages that become upregulated as the disease progresses. High ratios of premature oligodendrocytes expressing low levels of genes encoding major myelin protein components are characteristic of late disease stages and may represent a unique signature of C9orf72 ALS/FTD. Microglia with increased reactivity and astrocyte specific transcriptome changes in genes involved in glucose/glycogen metabolism are also associated with disease progression. Late stages of C9orf72 ALS/FTD correlate with sequential changes in the regulatory landscape of several genes in glial cells, namely MBP/MAG/MOG in oligodendrocytes, CD83/IRF8 in microglia, and GLUT1/GYS2/AGL in astrocytes. Only layer 2-3 cortical projection neurons with high expression of CUX2/LAMP5 are significantly reduced in C9orf72 ALS/FTD patients with respect to controls. Our findings reveal previously unknown progressive functional changes in cortical cells of C9orf72 ALS/FTD patients that shed light on the mechanisms underlying the pathology of this 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/2022.12.30.522259v1?rss=1 Authors: Ortega, J. A., Sasselli, I. R., Boccitto, M., Fleming, A. C., Fortuna, T. R., Li, Y., Sato, K., Clemons, T. D., Daley, E. L., Nguyen, T. P., Anderson, E. N., Ichida, J., Pandey, U. B., Wolin, S., Stupp, S. I., Kiskinis, E. Abstract: Amyotrophic lateral sclerosis and frontotemporal dementia patients with a hexanucleotide repeat expansion in C9ORF72 (C9-HRE) accumulate poly-GR and poly-PR aggregates. The pathogenicity of these arginine-rich dipeptide repeats (R-DPRs) is thought to be driven by their propensity to bind to low complexity domains of multivalent proteins. However, the ability of R-DPRs to bind native RNA and the significance of this interaction remains unclear. We used computational and experimental approaches to characterize the physicochemical properties of R-DPRs and their interaction with RNA. We find that poly-GR predominantly binds ribosomal RNA (rRNA) in cells and exhibits an interaction that is predicted to be energetically stronger than that for associated ribosomal proteins. Critically, modified rRNA 'bait' oligonucleotides restore poly-GR-associated ribosomal deficits in cells and ameliorate poly-GR toxicity in patient neurons and Drosophila models. Our work strengthens the hypothesis that ribosomal function is impaired by R-DPRs, highlights a role for direct rRNA binding in mediating ribosomal disfunction, and presents a strategy for protecting against C9-HRE pathophysiological mechanisms. 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/2022.11.16.516763v1?rss=1 Authors: Godfrey, R. K., Bjork, R. T., Alsop, E., Ruvalcaba, H. C., Antone, J., Michael, A. F., Williams, C., Hala'ufia, G., Blythe, A. D., Hall, M., Van Keuren-Jensen, K., Zarnescu, D. C. Abstract: Amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) comprise a spectrum of neurodegenerative diseases linked to TDP-43 proteinopathy. At the cellular level, TDP-43 proteinopathies are characterized by loss of nuclear TDP-43 and accumulation of cytoplasmic TDP-43 puncta that ultimately cause RNA processing defects including dysregulation of splicing, mRNA transport and translation. Complementing our previous models of ALS, here we report a novel model of FTD based on overexpression of TDP-43 in the Drosophila mushroom body (MB) circuit. This model recapitulates several aspects of FTD pathology including age dependent nuclear depletion and cytoplasmic accumulation of TDP-43 accompanied by behavioral deficits in working memory and sleep that occur before axonal degeneration ensues. RNA immunoprecipitations identify several candidate mRNA targets of TDP-43 in MBs, some of which are specific to the MB circuit and others that are shared with motor neurons. Using genetic interactions we show that overexpression of Dally-like-protein (Dlp), a modulator of Wg/Wnt signaling in MBs mitigates TDP-43 dependent working memory deficits. These results highlight the utility of modelling TDP-43 proteinopathy in Drosophila and provide a novel platform for studying the molecular mechanisms underlying FTD, and potentially uncovering circuit specific vulnerabilities in ALS/FTD. 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/2022.11.01.514717v1?rss=1 Authors: Fujino, Y., Ueyama, M., Ishiguro, T., Ozawa, D., Sugiki, T., Ito, H., Murata, A., Ishiguro, A., Gendron, T., Mori, K., Tokuda, E., Taminato, T., Konno, T., Koyama, A., Kawabe, Y., Takeuchi, T., Furukawa, Y., Fujiwara, T., Ikeda, M., Mizuno, T., Mochizuki, H., Mizusawa, H., Wada, K., Ishikawa, K., Onodera, O., Nakatani, K., Taguchi, H., Petrucelli, L., Nagai, Y. Abstract: Abnormal expansions of GGGGCC repeat sequence in the noncoding region of the C9orf72 gene is the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). The expanded repeat sequence is translated into dipeptide repeat proteins (DPRs) by noncanonical repeat-associated non-AUG (RAN) translation. Since DPRs play central roles in the pathogenesis of C9-ALS/FTD, we here investigate the regulatory mechanisms of RAN translation, focusing on the effects of RNA-binding proteins (RBPs) targeting GGGGCC repeat RNAs. Using C9-ALS/FTD model flies, we demonstrated that the ALS/FTD-linked RBP FUS suppresses RAN translation and neurodegeneration in an RNA-binding activity-dependent manner. Moreover, we found that FUS directly binds to and modulates the G-quadruplex structure of GGGGCC repeat RNA as an RNA chaperone, resulting in the suppression of RAN translation in vitro. These results reveal a previously unrecognized regulatory mechanism of RAN translation by G-quadruplex-targeting RBPs, providing therapeutic insights for C9-ALS/FTD and other repeat expansion diseases. 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/2022.10.31.514355v1?rss=1 Authors: Kim, S. H., Nichols, K. D., Anderson, E. N., Liu, Y., Ramesh, N., Jia, W., Kuerbis, C. J., Scalf, M., Smith, L. M., Pandey, U. B., Tibbetts, R. S. Abstract: Mutations in the ubiquitin (Ub) chaperone Ubiquilin 2 (UBQLN2) cause X-linked forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) through unknown mechanisms. Here we show that aggregation-prone, ALS-associated mutants of UBQLN2 (UBQLN2ALS) trigger heat stress-dependent neurodegeneration in Drosophila. A genetic modifier screen implicated endolysosomal and axon guidance genes, including the netrin receptor, Unc-5, as key modulators of UBQLN2 toxicity. Reduced gene dosage of Unc-5 or its coreceptor Dcc/frazzled diminished neurodegenerative phenotypes, including motor dysfunction, neuromuscular junction defects, and shortened lifespan, in flies expressing UBQLN2ALS alleles. Induced pluripotent stem cells (iPSCs) harboring UBQLN2ALS knockin mutations exhibited lysosomal defects while inducible motor neurons (iMNs) expressing UBQLN2ALS alleles exhibited cytosolic UBQLN2 inclusions, reduced neurite complexity, and growth cone defects that were partially reversed by silencing of UNC5B and DCC. The combined findings suggest that altered growth cone dynamics are a conserved pathomechanism in UBQLN2-associated ALS/FTD. 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/2022.10.04.510780v1?rss=1 Authors: van Tartwijk, F. W., Wunderlich, L. C. S., Mela, I., Makarchuk, S., Jakobs, M. A. H., Qamar, S., Franze, K., Kaminski Schierle, G. S., St George-Hyslop, P. H., Lin, J. Q., Holt, C. E., Kaminski, C. F. Abstract: Aberrant condensation and localisation of the RNA-binding protein fused in sarcoma (FUS) occur in variants of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS is also associated with cytoskeletal defects, genetically and through observations of compromised axonal transport. Here, we asked whether compromised axonal cytoskeletal organisation is an early feature of FUS-associated ALS/FTD. We used an ALS-associated mutant FUS(P525L) and the FTD-mimic hypomethylated FUS, FUS(16R), to investigate the common and distinct cytoskeletal changes found in these two reported Xenopus models. Combining a novel atomic force microscopy (AFM)-based approach for in vitro cytoskeletal characterisation and in vivo axonal branching analysis, we found that mutant FUS reduced actin density in the dynamically remodelling growth cone, and reduced axonal branch complexity. We furthermore found evidence of an axon looping defect for FUS(P525L). Therefore, we show that compromised actin remodelling is potentially an important early event in FUS-associated pathogenesis. 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/2022.09.30.510384v1?rss=1 Authors: cicardi, M. e., Kankate, V., Sriramoji, S., Krishnamurthy, K., ShamamandriMarkandaiah, S., Verdone-Morris, B., Girdhar, A., Nelson, A. T., Rivas, L. B., Boehringer, A., Haeusler, A., Pasinelli, P., Guo, L., Trotti, D. Abstract: A common cause of amyotrophic lateral sclerosis and frontotemporal dementia is the presence of a G4C2 intronic expansion in the C9orf72 gene. This expansion is translated by a non-AUG-dependent mechanism into five different dipeptide repeat proteins (DPRs), including the aggregation-prone poly glycine-arginine (GR), which is neurotoxic. Poly(GR) was found to interact with the nuclear importin Kap{beta}2 in non-neuronal cell lines. However, whether this interaction also occurs in neurons impacting their survival has not been studied. Here, we demonstrated that Kap{beta}2 and poly(GR) co-aggregate in neurons in-vitro and in-vivo in CNS tissue. Moreover, we showed that Kap{beta}2 mitigates poly(GR) neurotoxicity. Indeed, overexpression of Kap{beta}2 relieved poly(GR)-mediated neurotoxicity and restored nuclear TDP-43 levels, whereas silencing Kap{beta}2 increased the risk of death of neurons expressing poly(GR), suggesting that Kap{beta}2 plays a critical role in neurodegeneration. These findings open a new therapeutic avenue in C9-linked ALS/FTD focused on modulating Kap{beta}2 levels. 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/2022.09.19.508444v1?rss=1 Authors: Resnick, S. J., Qamar, S. S., Sheng, J., Huang, L. H., Nixon-Abell, J., Melore, S., Chung, C. W., Li, X., Wang, J., Zhang, N., Shneider, N. A., Kaminski, C. F., Ruggeri, F. S., Schierle, G. S. K., St George-Hyslop, P., Chavez, A. Abstract: Neurodegenerative disorders are a family of diseases that remain poorly treated despite their growing global health burden. A shared feature of many neurodegenerative disorders is the accumulation of toxic misfolded proteins. To gain insight into the mechanisms and modulators of protein misfolding, we developed a multiplex reverse genetics platform. Using this novel platform 29 cell-based models expressing proteins that undergo misfolding in neurodegeneration were probed against more than a thousand genetic modifiers. The resulting data provide insight into the nature of modifiers that act on multiple misfolded proteins as compared to those that show activity on only one. To illustrate the utility of this platform, we extensively characterized a potent hit from our screens, the human chaperone DNAJB6. We show that DNAJB6 is a general modifier of the toxicity and solubility of multiple amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD)-linked RNA-binding proteins (RBPs), including FUS, TDP-43, and hnRNPA1. Biophysical examination of DNAJB6 demonstrated that it co-phase separates with, and alters the behavior of FUS containing condensates by locking them into a loose gel-like state which prevents their fibrilization. Domain mapping and a deep mutational scan of DNAJB6 support the critical importance for DNAJB6 phase separation in its effects on multiple RNA-binding proteins. Crucially, these studies also suggest that this property can be further tuned to generate novel variants with enhanced activity that might illuminate potential avenues for clinical translation. 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/2020.09.15.298455v1?rss=1 Authors: Sidibe, H., Khalfallah, Y., Xiao, S., Gomez, N., Tank, E. M. H., Di Tomasso, G., Bareke, E., Aulas, A., McKeever, P. M., Melamed, Z., Destroismaisons, L., Deshaies, J.-E., Zinman, L., Parker, J. A., Legault, P., Tetreault, M., Barmada, S. J., Robertson, J., Vande Velde, C. Abstract: TDP-43 nuclear depletion and concurrent cytoplasmic accumulation in vulnerable neurons is a hallmark feature of progressive neurodegenerative proteinopathies such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cellular stress signalling and stress granule dynamics are now recognized to play a role in ALS/FTD pathogenesis. Defective stress granule assembly is associated with increased cellular vulnerability and death. G3BP1 (Ras-GAP SH3-domain-binding protein 1) is a critical stress granule assembly factor. Here, we define that TDP-43 stabilizes G3BP1 transcripts via direct binding of a highly conserved cis regulatory element within the 3'UTR. Moreover, we show in vitro and in vivo that nuclear TDP-43 depletion is sufficient to reduce G3BP1 protein levels. Finally, we establish that G3BP1 transcripts are reduced in ALS/FTD patient neurons bearing TDP-43 cytoplasmic inclusions/nuclear depletion. Thus, our data suggest that, in ALS/FTD, there is a compromised stress granule response in disease-affected neurons due to impaired G3BP1 mRNA stability caused by TDP-43 nuclear depletion. These data implicate TDP-43 and G3BP1 loss of function as contributors to disease. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.03.277459v1?rss=1 Authors: Lorenzini, I., Alsop, E., Levy, J., Gittings, L. M., Rabichow, B. E., Lall, D., Moore, S., Bustos, L., Pevey, R., Burciu, C., Saul, J., McQuade, A., Tzioras, M., Mota, T. A., Logemann, A., Rose, J., Almeida, S., Gao, F.-B., Bowser, R., Spires-Jones, T. L., Blurton-Jones, M., Gendron, T. F., Baloh, R. H., Van Keuren-Jensen, K., Sattler, R. Abstract: Background: A mutation in the C9orf72 gene is the most common genetic mutation of familial and sporadic ALS, as well as familial FTD. While prior studies have focused on elucidating the mechanisms of neuronal dysfunction and neurodegeneration associated with this genetic mutation, the contribution of microglia to disease pathogenesis in the ALS/FTD disease spectrum remains poorly understood. Methods: Here, we generated a new disease model consisting of cultured C9orf72 ALS/FTD patient-derived induced pluripotent stem cells differentiated into microglia (iPSC-MG). We used this model to study the intrinsic cellular and molecular phenotypes of microglia triggered by the C9orf72 gene mutation. Results: We show that C9orf72 ALS/FTD iPSC-MG have a similar transcriptional profile compared to control iPSC-MG, despite the presence of C9orf72-associated phenotypes including reduced C9orf72 protein levels and dipeptide-repeat protein translation. Interestingly, C9orf72 ALS/FTD iPSC-MG exhibit intrinsic dysfunction of phagocytic activity upon exposure to A{beta} or brain synaptoneurosomes and display a heightened inflammatory response. Detailed analysis of the endosomal and lysosomal pathways revealed altered expression of endosomal marker early endosome antigen 1 and lysosomal associated membrane protein 1 in C9orf72 ALS/FTD iPSC-MG, which was confirmed in patient postmortem tissues. Conclusions: These findings demonstrate that unstimulated C9orf72 iPSC-MG mono-cultures share a largely similar transcriptome profile with control microglia, despite the presence of C9orf72 disease phenotypes. The dysfunction of the endosomal-lysosomal pathway as demonstrated by aberrant microglia phagocytosis and engulfment of cellular debris and brain pathogens suggests that disease-related microglia phenotypes are not intrinsic but instead require microglia to be activated. In summary, the C9orf72 iPSC-MG culture system provides a novel human disease model to study the role of microglia in C9orf72 ALS/FTD disease pathogenesis. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.08.129528v1?rss=1 Authors: Pasetto, L., Pozzi, S., Micotti, E., Cerovic, M., Carli, M., Forloni, G., Bonetto, V. Abstract: Frontotemporal dementia (FTD) is a common cause of early-onset dementia, characterized by frontotemporal lobar degeneration and considerable clinical, genetic and neuropathological heterogeneity. Several mouse models of FTD have been generated targeting genes with known pathogenic roles. However, each of these models recapitulates only certain aspects of the human disease. Cyclophilin A (PPIA) is a multifunctional protein abundantly expressed in the brain, with double-edged functions. Intracellularly, it is mainly protective as a foldase and molecular chaperone with scaffolding properties. Extracellularly, it behaves as a proinflammatory cytokine able to activate an aberrant inflammatory response. In a previous work, we found that PPIA governs TDP-43 functions and its deficiency exacerbates disease in a mouse model of ALS. Selective inhibition of extracellular PPIA rescued motor neurons and increased survival. To decipher PPIA functions in the central nervous system, we planned a deep neuropathological and behavioral characterization of PPIA knock-out (PPIA-/-) mice throughout their lifespan. They develop a neurodegenerative disease that recapitulates key features of the behavioral variant of FTD associated with TDP-43 pathology. PPIA-/- mice present progressive hippocampal and cortex atrophy, with neuronal death and clear-cut TDP-43 pathology that include fragmentation, hyperphosphorylation, and cytoplasmic mislocalization/nuclear clearing. Mice exhibit increased disinhibition, defects in social behavior, but no memory and motor impairment. On a molecular level, our findings indicate that PPIA is involved in multiple genes and pathways that have a dominant protective effect in the brain, and is fundamental for TDP-43 function. Considering that an impaired interaction of TDP-43 with PPIA has been observed in ALS/FTD patients, the PPIA-/- mouse is a useful experimental model to investigate the mechanism at the basis of TDP-43 pathology and develop novel therapeutic approaches for ALS/FTD and possibly other TDP-43 proteinopathies. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.04.133546v1?rss=1 Authors: Sun, X., Deng, X., Hu, R., Duan, Y., Zhang, K., Cui, J., Ni, J., Wang, Q., Chen, Y., Li, A., Fang, Y. Abstract: Protein inclusions containing phosphorylated TDP-43 are a shared pathology in several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, most ALS/FTD patients do not have a mutation in TDP-43 or the enzymes directly regulating its phosphorylation. It is intriguing how TDP-43 becomes hyperphosphorylated in each disease condition. In a genetic screen for novel TDP-43 modifiers, we found that knockdown (KD) of CHMP2B, a key component of the endosomal sorting complex required for transport (ESCRT) machinery, suppressed TDP-43-mediated neurodegeneration in Drosophila. Further investigation using mammalian cells indicated that CHMP2B KD decreased whereas its overexpression (OE) increased TDP-43 phosphorylation levels. Moreover, a known FTD-causing mutation CHMP2Bintron5 promoted hyperphosphorylation, insolubility and cytoplasmic accumulation of TDP-43. Interestingly, CHMP2B did not manifest these effects by its well-known function in the autophagy-lysosomal pathway. Instead, the kinase CK1 tightly regulated TDP-43 phosphorylation level in cells, and CHMP2B OE or CHMP2BIntron5 significantly decreased ubiquitination levels and the turnover of CK1 via the ubiquitin-proteasome (UPS) pathway. Finally, we showed that CHMP2B protein levels increased in the cerebral cortices of aged mice, which might underlie the age-associated TDP-43 pathology and disease onset. Together, our findings reveal a molecular link between the two ALS/FTD-pathogenic proteins CHMP2B and TDP-43, and provide an autophagy-independent mechanism for CHMP2B in pathogenesis. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.24.107177v1?rss=1 Authors: Lin, Z., Kim, E., Ahmed, M., Han, G., Simmons, C., Redhead, Y., Bartlett, J., Altamira, L. E. P., Callaghan, I., White, M., Singh, N., Sawiak, S., Spires-Jones, T., Vernon, A. C., Coleman, M., Green, J. B. A., Henstridge, C., Davies, J. S., Cash, D., Sreedharan, J. Abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping neurodegenerative diseases that are increasingly understood to have long prodromal periods. Investigation of these early stages promises to yield valuable biomarkers of disease and will be key to understanding mechanisms underlying the genesis of ALS-FTD. Here, we use in vivo magnetic resonance imaging (MRI), histology and computed tomography to identify structural and cellular readouts of early stage disease in the TDP-43Q331K knock-in mouse model of ALS-FTD. Adult mutant mice demonstrated parenchymal volume reductions affecting the frontal lobe and entorhinal cortex in a manner reminiscent of ALS-FTD. Subcortical, cerebellar and brain stem regions were also affected in line with observations in presymptomatic carriers of mutations in C9orf72, the commonest genetic cause of both ALS and FTD. Volume loss, as measured by MRI, was also observed in the dentate gyrus (DG) of the hippocampus, along with ventricular enlargement. Guided by these imaging findings, detailed post-mortem brain tissue analysis revealed reduced parvalbumin-positive (PV+) interneurons as a potential cellular correlate of MRI changes in mutant mice. By contrast, microglia were in a disease activated state even in the absence of brain volume loss. A reduction in immature neurons was found in the DG, indicative of impaired adult neurogenesis, while a paucity of PV+ interneurons in juvenile mutant mice (P14) suggests that TDP-43Q331K disrupts neurodevelopment. Computerised tomography imaging also showed altered skull morphology in mutants, further suggesting a role for TDP-43Q331K in development. Finally, analysis of human post-mortem prefrontal cortices confirmed a paucity of PV+ interneurons in the prefrontal cortex in cases with both sporadic ALS and ALS linked to C9orf72 mutations. This study suggests an important role for PV+ interneurons in regional brain vulnerability associated with ALS-FTD, and identifies novel MRI and histological biomarkers that will be of value in assessing the efficacy of putative therapeutics in TDP-43Q331K knock-in mice. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.30.071365v1?rss=1 Authors: Rayner, S. L., Cheng, F., Yang, S., Grima, N., Ke, Y. D., Au, C. G., Morsch, M., De Luca, A., Davidson, J. M., Molloy, M. P., Shi, B., Ittner, L. M., Blair, I., Chung, R. S., Lee, A. Abstract: Background: Previously, we identified missense mutations in CCNF that are causative of familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). CCNF encodes for the protein cyclin F, a substrate recognition component of the E3-ubiquitin ligase, SCFcyclin F. We have previously shown that mutations in CCNF cause disruptions to overall protein homeostasis; causing a build-up of ubiquitylated proteins (1) as well as defects in autophagic machinery (2). Methods: Here, we have used an unbiased proteomic screening workflow using BioID, as well as standard immunoprecipitations to identify novel interaction partners of cyclin F, identifying the interaction between cyclin F and a series of paraspeckle proteins. The homeostasis of these new cyclin F interaction partners, RBM14, NONO and SFPQ were monitored in primary neurons using immunoblotting. In addition, the homeostasis of RBM14 was compared between control and ALS/FTD patient tissue using standard IHC studies. Results: Using BioID, we found over 100 putative interaction partners of cyclin F and demonstrated that cyclin F closely associates with a number of essential paraspeckle proteins, which are stress-responsive proteins that have recently been implicated in ALS pathogenesis. We further demonstrate that the turnover of these novel binding partners are defective when cyclin F carries an ALS/FTD-causing mutation. In addition the analysis of RBM14 levels in ALS patient post-mortem tissue revealed that RBM14 levels were significantly reduced in post-mortem ALS patient motor cortex and significantly reduced in the neurons of spinal cord tissue. Conclusion: Overall, our data demonstrate that the dysregulation of paraspeckle components may be contributing factors to the molecular pathogenesis of ALS/FTD. Copy rights belong to original authors. Visit the link for more info

Sandrine Da Cruz, PhD and Jone López-Erauskin, PhD explain how ALS causing mutations in FUS inhibit intra-axonal protein synthesis and drive disease without nuclear loss of FUS function. This research appears in the journal Neuron. [Health and Medicine] [Science] [Show ID: 34203]

Sandrine Da Cruz, PhD and Jone López-Erauskin, PhD explain how ALS causing mutations in FUS inhibit intra-axonal protein synthesis and drive disease without nuclear loss of FUS function. This research appears in the journal Neuron. [Health and Medicine] [Science] [Show ID: 34203]

Sandrine Da Cruz, PhD and Jone López-Erauskin, PhD explain how ALS causing mutations in FUS inhibit intra-axonal protein synthesis and drive disease without nuclear loss of FUS function. This research appears in the journal Neuron. [Health and Medicine] [Science] [Show ID: 34203]

Sandrine Da Cruz, PhD and Jone López-Erauskin, PhD explain how ALS causing mutations in FUS inhibit intra-axonal protein synthesis and drive disease without nuclear loss of FUS function. This research appears in the journal Neuron. [Health and Medicine] [Science] [Show ID: 34203]

Tibor Hortobagyi - Department of Neuropathology, Institute of Pathology, University of Debrecen, Debrecen, HUNGARY speaks on “Pathology and current molecular classification of ALS/FTD”. This seminar has been recorded by ICGEB Trieste

Neurodegenerative disease patients suffer from cognitive decline and/or motor dysfunctions, depending on the different regions affected by the neuron loss. With aging being the major risk factor and a society with increased life expectancy, there is an urgent need to develop new effective treatments to alleviate the situation faced by patients, their families and society. Although neurodegenerative diseases including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD) lead to different clinical symptoms, they share common pathomechanisms, such as protein aggregation and altered RNA metabolism. A subset of ALS and FTD cases, for instance, is pathologically characterized by neuronal cytoplasmic inclusions containing aggregated Fused in Sarcoma (FUS) protein. There is also a genetic link, since FUS mutations cause ALS with FUS pathology. FUS is a DNA/RNA-binding protein known to regulate different steps of RNA metabolism, however, its exact function and target genes in neurons were unknown. In this study, I evaluated the neuronal role of FUS in alternative splicing using a candidate approach focusing on the microtubule-associated protein TAU. TAU is one of the most widely studied proteins in neurodegeneration research due to its aggregation in different tauopathies, most notably AD. Mutations in the TAU gene MAPT, that affect alternative splicing of exon 10, are known to cause another subtype of FTD. Here, I demonstrate that FUS depleted rat neurons, although having normal viability, show aberrant alternative splicing of TAU, with increased inclusion of exon 3 and exon 10, resulting in higher expression of the 2N and 4R TAU isoforms. Importantly, reintroduction of human FUS rescues aberrant splicing of TAU in FUS depleted neurons. Accordingly, overexpression of FUS decreases expression of 2N and 4R TAU isoforms. In mouse brain lysates, I detected direct FUS binding to TAU pre-mRNA, with strong binding around the regulated exon 10, often at AUU-rich RNA stretches. Since TAU splicing is regulated differently in humans and rodents, I also confirmed the role of human FUS in TAU exon 10 splicing using a TAU minigene and a human neuronal cell line. In addition, I analyzed the morphology and development of axons to evaluate the functional consequences of FUS depletion in neurons. Although FUS depleted neurons develop neurites normally, their axons are significantly shorter than in the control cells. Similar to observations in TAU/MAP1B knockout neurons, axons of FUS depleted neurons develop significantly larger growth cones with abnormal cytoskeletal organization. The development of growth cones in vivo is an essential step in axonal maintenance and repair. Altogether, this study identified TAU as the first physiological splice target of FUS in neurons. The newly discovered role of FUS in regulating the axonal cytoskeleton indicates that aberrant axonal function could contribute to the neuron loss seen in ALS/FTD cases with FUS aggregates.

Davide Trotti, Department of Neuroscience & Farber Institute for Neuroscience, Thomas Jefferson University, Philadelphia - USA speaks on "Neuronal toxicity of the ALS/FTD-linked GGGGCC repeat expansions within the C9ORF72 gene - RNA Metabolism: Changing Paradigms in Neurodegeneration” This seminar has been recorded at Area Science Park Trieste by ICGEB Trieste

Vincenzo Silani, Istituto Auxologico Italiano, U.O. Neurologia – Stroke Unit e Laboratorio Neuroscienze, Milano - ITALY speaks on "From TARDBP and FUS/TLS to C9orf72 in ALS/FTD: further changing paradigms in the genotype-phenotype correlation - RNA Metabolism: Changing Paradigms in Neurodegeneration". This seminar has been recorded at Area Science Park Trieste by ICGEB Trieste