Podcasts about c9orf72

What happens when you learn that your DNA carries the same mutation that led to a loved one's battle with ALS? In this episode, I sit down with Mindy Uhrlaub, who discovered she is a carrier of the C9orf72 gene—the most common genetic cause of ALS and Frontotemporal Dementia. Mindy shares her emotional journey of genetic testing, the weight of living in the unknown and the unique challenges that come with being pre-symptomatic.We dive into the mental and emotional impact of her hereditary disease, the stigma surrounding genetic conditions, and how humor, advocacy and community can help navigate these uncertainties. Mindy also talks about her work with End the Legacy, a patient led organization dedicated to the needs and interests of the Genetic ALS & FTD community.This powerful conversation is a reminder that while genetics may shape our path, they don't define who we are. Tune in for an honest, hopeful discussion about fear, resilience and finding purpose in the face of the unknown.  Listen in and share with a friend.  Hugs, LorriFollow and see what's coming next: Instagram, Facebook, Twitter, TikTok, LinkedIn.

In this insightful episode of Research Renaissance, host Deborah Westphal engages in an enlightening conversation with Dr. Zhe Zhang, a research associate at Johns Hopkins and a 2021 Toffler Scholar. Dr. Zhang discusses her journey from aspiring to be a doctor to becoming a dedicated researcher focused on neurodegenerative diseases, particularly ALS. She shares her innovative work on establishing a platform to find genetic modifiers that can improve cell survival and slow the progression of ALS.Key Discussion Points:Introduction to Dr. Zhe Zhang:Background and inspiration for pursuing research in neurodegenerative diseases.Transition from clinical practice to basic research.Journey to ALS Research:Initial interest sparked by experiences with neurodegenerative patients during medical training.Shift in focus during her time in Australia, influenced by collaborations and the Ice Bucket Challenge.Focus on Genetic Modifiers and ALS:Explanation of familial and sporadic ALS, with a focus on the C9ORF72 gene mutation.Development of toxic proteins from gene mutations and their impact on cell survival.Research Techniques and Platforms:Use of CRISPR technology for genetic screening and identifying potential therapeutic targets.Application of human induced pluripotent stem cells (iPSCs) to develop models for screening.Collaborative Efforts:Importance of interdisciplinary collaborations with other researchers and biobanks.Contributions from patient-donated post-mortem tissues to validate research findings.Challenges and Future Directions:The complexity of translating basic research to clinical applications and commercial products.The role of CRISPR in gene editing and its potential for therapeutic interventions.Emerging Technologies and Tools:The impact of iPSCs, CRISPR, and advanced imaging techniques on ALS research.Potential of functional MRI and other non-invasive methods for tracking disease progression.Global Collaboration and Impact:The necessity of global studies and collaborations to understand neurodegenerative diseases.Hopes for future research, including the development of effective therapies for ALS.Personal Reflections and Advice:Dr. Zhang's commitment to staying curious, passionate, and cautious in her research.Encouragement for young researchers to persevere despite challenges and to collaborate widely.Join us in advancing our understanding of the brain and addressing its ailments. Until then, onward and upward!To learn more about the breakthroughs discussed in this episode and to support ongoing research, visit our website at tofflertrust.org. Technical Podcast Support by Jon Keur at Wayfare Recording Co.

Episode 152: ALS FundamentalsFuture Dr. Rodriguez explains the symptoms of ALS, including UMN and LMN symptoms. Dr. Arreaza discusses the principles of symptomatic treatment by primary care. This is a brief introduction to ALS.  Written by Adraina Rodriguez, MSIV, Ross University School of Medicine.  You are listening to Rio Bravo qWeek Podcast, your weekly dose of knowledge brought to you by the Rio Bravo Family Medicine Residency Program from Bakersfield, California, a UCLA-affiliated program sponsored by Clinica Sierra Vista, Let Us Be Your Healthcare Home. This podcast was created for educational purposes only. Visit your primary care provider for additional medical advice.Arreaza: It is rare but you may encounter it and you should be able to identify the most common symptoms. ALS Challenge in 2014: Ice bucket challenge. Adriana: Patrick Quinn was an ALS patient and activist who created the ICE Bicket Challenge and helped raise US$220 million for medical research.Arreaza: What is ALS?Adriana: ALS stands for Amyotrophic Lateral Sclerosis, formerly known as Lou Gehrig's Disease. It is the most common form of acquired motor neuron disease. ALS is a progressive, incurable neurodegenerative motor neuron disorder with Upper motor neuron (UMN) and/or Lower motor neuron symptoms that cause muscle weakness, disability, and eventually death. There is no single diagnostic test that can confirm or entirely exclude the diagnosis of motor neuron disease. Arreaza: When should you suspect ALS in a patient?Adriana: The classic patient presentation is insidious, slowly progressive, and unremitting UMN and/or LMN symptoms present in one of four body segments - cranial/bulbar, cervical, thoracic, and lumbosacral - followed by spread to other segments over a period of months to years. Arreaza: What would you see on the physical exam when the Patient is in the clinic? There is a system to send signals from your brain to your muscles. It involves basically two neurons: Upper and lower motor neurons. The UMN goes from your cerebral cortex to your spinal cord and there it connects to a lower motor neuron through synapsis. The LMN then sends the signal to your muscles, causing contraction or relaxation. Tell us about the UMN and LMN symptoms.Adriana:LMN Symptoms: Weakness, Fasciculations, Muscular atrophy, Decreased muscle tone (flaccidity) and reduced or absent reflexes. UMN Symptoms: Increased tone and increased extremity deep-tendon reflexes, presence of any reflexes in muscles that are profoundly weak and wasted, pathological reflexes (crossed adductors, jaw jerk, Hoffman sign, Babinski sign 50%), syndrome of pseudobulbar affect (inappropriate laughing, crying, forced yawning).Arreaza: What are important factors to help narrow your differential to ALS?Multifocal motor neuropathy, cervical radiculomyelopathy, benign fasciculations, inflammatory myopathies, post-polio syndrome, monomelic amyotrophy, hereditary spastic paraplegia, spinobulbar muscular atrophy, myasthenia gravis, hyperthyroidism, and many others.There are pertinent negatives to look out for: Usually negative neuropathic or radiculopathic pain, sensory loss, sphincter dysfunction, ptosis, or extraocular muscle dysfunction (20-30% positive sensory symptoms or “pins and needles” and “electricity” in the affected limbs).Note: Cognitive dysfunction does not exclude ALSArreaza: What are the diagnostic criteria for ALSAdriana: Gold Coast Criteria 2019 proposed over El Escorial criteria:Progressive upper and lower motor neuron symptoms and signs in one limb or body segment, ORProgressive lower motor neuron symptoms and signs in at least two body segments, ANDAbsence of electrophysiologic, neuroimaging, and pathologic evidence of other disease processes that might explain the signs of lower and/or upper motor neuron degeneration.Arreaza: What diagnostic tests should be ordered for further evaluation?Adriana: Electrodiagnostic studies: Electromyogram and nerve conduction studies (EMG and NCS)Laboratory testing: creatine phosphokinase up to 1000u/LNeuroimaging: to exclude other causes mainly. Brain MRI whenever bulbar disease is present. Cervical and lumbosacral spine MRI for LMN findings in the arms and legs.Genetic testing: FALS 10% of ALS defect in C9ORF72 gene that makes motor neuron and brain nerve cell protein, the exact cause is unknown. Arreaza: Finally, how do you treat ALS?Adriana: Disease-modifying treatment: Riluzole is recommended for all patients with ALS. Shown to prolong survival and slow functional deterioration. The mechanisms of action that reduce glutamate-induced excitotoxicity: 1) inhibit glutamic acid release, 2) non-competitive block of N-methyl-D-aspartate (NMDA) receptor-mediated responses, 3) direct action on the voltage-dependent sodium channel. Arreaza: Riluzole is given 50 mg by mouth twice a day. It may cause drowsiness or somnolence, hepatic injury: Not recommended for patients with elevation of transaminases >5 times the upper limit of normal. It is recommended to monitor for hepatic injury and discontinue if there is evidence of liver dysfunction, such as hyperbilirubinemia.Adriana: Symptom-based management is the mainstay of treatment. You may involve a multidisciplinary team to treat the symptoms. For example: palliative, hospice, respiratory function management (Noninvasive Positive Pressure Ventilation vs mechanical ventilation.Arreaza: PCPs may be in charge of managing symptoms because you are the closest provider to the patient. Wherever available, it is recommended to refer your ALS patients to a specialized center. Many patients do not have availability to an ALS center or a neurologist, but they have you to manage their symptoms or complications.Adriana: Dysphagia: It is a common and distressing symptom. It is suggested PEG tube placement for patients with ALS with normal or moderate respiratory function who have dysphagia. It is controversial, some studies found no benefit on survival or quality of life and other studies suggest that it is safe to give a high-carb, hypercaloric diet to ALS patients. Arreaza: Spasticity: Use medications such as baclofen and tizanidine may be helpful, and botulinum injections are an option for those who are not responding to oral muscle relaxants. Adriana: Sialorrhea: Use medications such as atropine, hyoscyamine, amitriptyline, and scopolamine. If these medications are not effective or tolerated, used botox injections into the salivary glands. It is considered safe and useful for treating sialorrhea in patients with ALS. Botox is not only for wrinkles!Arreaza: There are many other symptoms that will require management, but you are invited to review your preferred source of information such as Up to Date, AAFP, or the ALS Association website. ______________________________Conclusion: Now we conclude episode number 152, “ALS Fundamentals.” You heard from future Dr. Rodriguez that ALS can present with upper motor neuron symptoms, such as spastic muscles and hyperreflexia; or lower motor neuron symptoms, such as flaccid and weak muscles. Some other symptoms include dysphagia, shortness of breath, difficulty talking, fatigue, thick mucus, and pseudobulbar affect. Dr. Arreaza explained that primary care physicians are in a special situation to help diagnose and treat the symptoms of ALS, especially in communities with limited access to an ALS center. You may need to involve a multidisciplinary team to improve the quality of life and possibly the survival of ALS patients. This week we thank Hector Arreaza and Adriana Rodiguez. Audio editing by Adrianne Silva.Even without trying, every night you go to bed a little wiser. Thanks for listening to Rio Bravo qWeek Podcast. We want to hear from you, send us an email at RioBravoqWeek@clinicasierravista.org, or visit our website riobravofmrp.org/qweek. See you next week! _____________________References:Galvez-Jimenez, Nestor and Colin Quinn, Symptom-based management of amyotrophic lateral sclerosis, Up To Date, updated on July 31, 2023. https://www.uptodate.com/contents/symptom-based-management-of-amyotrophic-lateral-sclerosis. Royalty-free music used for this episode: Good Vibes: Sky's The limit, downloaded on July 20, 2023 from https://www.videvo.net/ 

Tieteen päivät 2023- tapahtumaa vietetään 26.08.2023 Kuopiossa. Itä-Suomen yliopisto järjestää tapahtuman Elonkorjuujuhlien yhteydessä Kuopion museon tiloissa sekä myös Kuopion torilla. Yksi käsiteltävä aihe tapahtumassa on aivoterveys, josta saimme kuulla taajuudella tarkemmin, kun Savon Aaltojen lauantaivieraaksi saapui tutkimusjohtaja Eino Solje. Solje on opiskellut lääketieteen lisensiaatiksi ja tohtoriksi Itä-Suomen yliopiston lääketieteen laitoksella. Soljen väitöskirja on julkaistu vuonna 2016, ja se käsittelee C9orf72-toistojaksomutaatioon liittyvää otsalohkodementiaa diagnostiikan ja hoidon näkökulmista. Aikaisemmin Solje on työskennellyt muun muassa Brescian yliopistossa Italiassa. Lisäksi hän on työskennellyt tutkimusjohtajana Itä-Suomen yliopistossa ja neurologina Kuopion yliopistollisessa sairaalassa. Solje on otsalohkodementian arvostettu tutkija ja luennoitsija. Vuonna 2021 Solje palkittiin vuoden nuorena kliinisenä tutkijana. Vuonna 2020 Solje kutsuttiin Lindau Nobel Laureate Meeting -kokoukseen. Lisäksi hänet on palkittu vuonna 2022 Martti Hämäläinen -palkinnolla. Haastattelijana: Sami Turunen

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

During this year's alumni reunion Partio, we caught up with some alums right on campus. One of those alumni was Daniel Barvin ‘18.Daniel has held many different roles, in both financial advising and oil and gas sectors, and eventually earned an MBA from Rice Business in 2018. But in December of that same year that he tested positive for the C9orf72 gene expansion, which means may develop ALS later in life. Daniel's father, aunt, and uncle all have ALS. In 2020, he began volunteering at I AM ALS, and also joined Coya Therapeutics, a clinical-stage cell therapy platform company developing first-in-class therapeutics for ALS and other neurodegenerative diseases, where he is currently VP of operations and patient advocacy.In this episode recorded in the Rice Alliance space in McNair Hall, Daniel chats with host Maya Pomroy '22 about his journey, his passion for ALS research, and building community and support online with others affected by this disease.Owl Have You Know is a production of Rice Business and is produced by University FM.Episode Quotes:Changing the future of what it means to have ALS through Coya27:20 - We are in this age where we all know someone who's dealt with a neurodegenerative disease… [27:32] And Coya is looking to change what that experience is, change what it means to be diagnosed with these diseases, and show that through Houston's effort, through Rice's effort, through all of our efforts, we can change the future of what it means to have this disease and have it not be a death sentence.How I AM ALS helped launch the movement18:01 - I AM ALS has the beauty of being patient-led, letting anyone who comes say, "We'll let you start a team. We'll provide resources in terms of team management." And that was just the perfect place for us to start this ferocious movement.Empowering ALS patients with his story11:34 - The silver lining was after we came back from vacation, I was asked to do a talk for a high school, helping explain my story after an ALS documentary was shown. And I went and spoke at Carnegie Vanguard High School in front of the entire student body—800 students—and told them the story of my life. And the connection was palpable. And I said, "This is it. This is what I need to be doing."On being intentional about relationships16:33 - What I said when I was doing the advocacy part, I said I'm going to make less ALS patients. I'm going to make better ALS patients because I think that if I eventually get this disease, The fact that I'm able to plan, prepare, connect, comprehend, you know, this entire life of advocacy, and then I eventually get it, my mindset will most likely be far different than someone who just has to live with it.Show Links:  Coya Therapeutics End The Legacy I AM ALS Transcript Guest Profile:LinkedIn

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

Bienvenue sur RARE à l'écoute, la chaîne de Podcast dédiée aux maladies rares. Pour ce troisième épisode sur la Sclérose Latérale Amyotrophique ou SLA, nous recevons le Pr Philippe Corcia, neurologue et coordonnateur du centre de référence SLA et autres maladies du neurone moteur du CHRU de Tours, sous l'égide de la filière FilSLAN. Nous abordons aujourd'hui l'aspect génétique de la SLA, la composante génétique et les mutations génétiques mises en évidence dans la SLA, le diagnostic de la maladie, ainsi que le conseil génétique à proposer aux patients et à leur famille. Si vous désirez vous informer et aller plus loin dans la connaissance de cette pathologie, nous vous donnons rendez-vous sur notre site internet www.rarealecoute.com. L'orateur n'a reçu aucune rémunération pour la réalisation de cet épisode.   Invité : Pr Philippe Corcia – CHU de Tours https://www.chu-tours.fr/etre-soigne-et-rendre-visite-a-un-patient/joindre-le-chru/liste-des-services/neurologie-hospitalisation/  L'équipe : Virginie Druenne - Programmation Cyril Cassard - Animation Hervé Guillot - Production Crédits : Sonacom

When we talk about ALS, we often make a distinction between types of the disease: 90% of cases appear to be sporadic – meaning there is no family history of the disease. The opposite is true of the other 10% – known as familial ALS or genetic ALS. In these cases, the disease can sometimes be traced back in a family for generations.  Behind this phenomenon are a number of inherited mutations in genes with names like SOD1, FUS, C9orf72. With the advent of widely available genetic testing, people with a family history of ALS are now able to find out if they carry these mutations – and are thus likely to develop the disease. When Jean Swidler was a child, she lost her grandmother to ALS. Then as, an adult, her mother was diagnosed with the disease. Eventually, Jean herself underwent genetic testing and discovered that she carries the C9orf72 repeat-expansion mutation.  Since then, Jean has become a tireless advocate for asymptomatic carriers of ALS-related genetic mutations. Today, she joins us to talk about her story, her advocacy, and how she believes the medical and research establishment could be better serving people in her situation. Support the show: https://www.als.net/donate/See omnystudio.com/listener for privacy information.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.16.528809v1?rss=1 Authors: Cicardi, M. E., Hallgren, J., Darilang, M., Krishnamurthy, K., Shamamandri Markandaiah, S., Nelson, A. T., Kankate, V., Anderson, E., Pasinelli, P., Pandey, U. B., Eischen, C. M., Trotti, D. Abstract: The ALS/FTD-linked intronic hexanucleotide repeat expansion in the C9orf72 gene is translated into dipeptide repeat proteins, among which poly-proline-arginine (PR) displays the most aggressive neurotoxicity in-vitro and in-vivo. PR partitions to the nucleus when expressed in neurons and other cell types. Using drosophila and primary rat cortical neurons as model systems, we show that by lessening the nuclear accumulation of PR, we can drastically reduce its neurotoxicity. PR accumulates in the nucleolus, a site of ribosome biogenesis that regulates the cell stress response. We examined the effect of nucleolar PR accumulation and its impact on nucleolar function and determined that PR caused nucleolar stress and increased levels of the transcription factor p53. Downregulating p53 levels, either genetically or by increasing its degradation, also prevented PR-mediated neurotoxic phenotypes both in in-vitro and in-vivo models. We also investigated whether PR could cause the senescence phenotype in neurons but observed none. Instead, we found induction of apoptosis via caspase-3 activation. In summary, we uncovered the central role of nucleolar dysfunction upon PR expression in the context of C9-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/2023.01.12.523820v1?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/2022.11.17.516859v1?rss=1 Authors: Li, J., Jaiswal, M. K., Chien, J.-F., Kozlenkov, A., Zhou, P., Gardashli, M., Pregent, L. J., Engelberg-Cook, E., Dickson, D. W., Belzil, V. V., Mukamel, E. A., Dracheva, S. Abstract: Neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are strongly influenced by inherited genetic variation, but environmental and epigenetic factors also play key roles in the course of these diseases. A hexanucleotide repeat expansion in the C9orf72 (C9) gene is the most common genetic cause of ALS and FTD. To determine the cellular alterations associated with the C9 repeat expansion, we performed single nucleus transcriptomics (snRNA-seq) and epigenomics (snATAC-seq) in postmortem samples of motor and frontal cortices from C9-ALS and C9-FTD donors. We found pervasive alterations of gene expression across multiple cortical cell types in C9-ALS, with the largest number of affected genes in astrocytes and excitatory neurons. Astrocytes increased expression of markers of activation and pathways associated with structural remodeling. Excitatory neurons in upper and deep layers increased expression of genes related to proteostasis, metabolism, and protein expression, and decreased expression of genes related to neuronal function. Epigenetic analyses revealed concordant changes in chromatin accessibility, histone modifications, and gene expression in specific cell types. C9-FTD patients had a distinct pattern of changes, including loss of neurons in frontal cortex and altered expression of thousands of genes in astrocytes and oligodendrocyte-lineage cells. Overall, these findings demonstrate a context-dependent molecular disruption in C9-ALS and C9-FTD, resulting in distinct effects across cell types, brain regions, and disease phenotypes. 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/2022.10.26.513909v1?rss=1 Authors: Masrori, P., Bijnens, B., Davie, K., Poovathingal, S. K., Storm, A., Hersmus, N., Fumagalli, L., Van Den Bosch, L., Fiers, M., Thal, D. R., Mancuso, R., Van Damme, P. Abstract: Neuroinflammation is an important hallmark in amyotrophic lateral sclerosis (ALS). Experimental evidence has highlighted a role of microglia in the modulation of motor neuron degeneration. However, the exact contribution of microglia to both sporadic and genetic forms of ALS is still unclear. We generated single nuclei profiles of spinal cord and motor cortex from sporadic and C9orf72 ALS patients, as well as controls. We particularly focused on the transcriptomic responses of both microglia and astrocytes. We confirmed that C9orf72 is highly expressed in microglia and shows a diminished expression in carriers of the hexanucleotide repeat expansion (HRE). This resulted in an impaired response to disease, with specific deficits in phagocytic and lysosomal transcriptional pathways. Astrocytes also displayed a dysregulated response in C9orf72 ALS patients, remaining in a homeostatic state. This suggests that C9orf72 HRE alters a coordinated glial response, which ultimately would increase the risk for developing ALS. Our results indicate that C9orf72 HRE results in a selective microglial loss-of-function, likely impairing microglial-astrocyte communication and preventing a global glial response. This is relevant as it indicates that sporadic and familial forms of ALS may present a different cellular substrate, which is of great importance for patient stratification and treatment. 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/2022.10.10.511318v1?rss=1 Authors: Balendra, R., Ruiz de los Mozos, I., Glaria, I., Milioto, C., Odeh, H. M., Wilson, K. M., Ule, A. M., Hallegger, M., Masino, L., Martin, S., Patani, R., Shorter, J., Ule, J., Isaacs, A. Abstract: An intronic GGGGCC repeat expansion in C9orf72 is a common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. The repeats are transcribed in both sense and antisense directions to generate distinct dipeptide repeat proteins, of which poly(GA), poly(GR) and poly(PR) have been implicated in contributing to neurodegeneration. Poly(PR) binding to RNA may contribute to toxicity, but analysis of poly(PR)-RNA binding on a genome-wide scale has not yet been carried out. We therefore performed crosslinking and immunoprecipitation (CLIP) analysis in human cells to identify the RNA binding sites of poly(PR). We found that poly(PR) binds to nearly 600 RNAs, with the sequence GAAGA enriched at the binding sites. In vitro experiments showed that polyGAAGA RNA binds poly(PR) with higher affinity than control RNA and induces phase-separation of poly(PR) into condensates. These data indicate that poly(PR) preferentially binds to polyGAAGA-containing RNAs, which may have physiological consequences. 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

Dr. Philip Wade Tipton discusses his paper, "Differences in Motor Features of C9orf72, MAPT, or GRN Variant Carriers With Familial Frontotemporal Lobar Degeneration". Show references: https://n.neurology.org/content/early/2022/06/29/WNL.0000000000200860 This podcast is sponsored by argenx. Visit www.vyvgarthcp.com for more information.

Dr. Matt Barrett talks with Dr. Philip Tipton about differences in motor features of C9orf72, MAPT, and GRN variant carriers with familial frontotemporal lobar degeneration. Read the full article in Neurology. This podcast is sponsored by argenx. Visit www.vyvgarthcp.com for more information.

Dr. Robert Brown discusses the Nature Medicine article, "Suppression of Mutant C9orf72 Expression by a Potent Mixed Backbone Antisense Oligonucleotide". Show references: https://www.nature.com/articles/s41591-021-01557-6

Dr. Jeff Ratliff discusses the suppression of mutant C9orf72 expression by a potent mixed backbone antisense oligonucleotide with Drs. Jonathan Watts and Robert Brown.

In this episode of the Genetics Podcast we're joined by Daniel Barvin, an ALS advocate whose family is affected by Familial ALS. Daniel has a genetic variant in the gene called C9orf72 that predisposes him to develop this neurodegenerative disease, and he talks about his experience getting genetic testing and decision with his wife to undergo IVF and pre-implantation genetic diagnosis to ensure that their child did not inherit the genetic variant. Daniel joins Patrick to discuss the lack of availability of genetic testing in ALS, how to make genetic testing more accessible, breaking down stigmas in hereditary disease, and his work with the non-profit 'I AM ALS'. Patrick also mentions the upcoming Festival Genomics with over 100 great speakers. You can find out more here: https://www.festivalofgenomics.com/

In this episode of the Genetics Podcast we’re joined by Daniel Barvin, an ALS advocate whose family is affected by Familial ALS. Daniel has a genetic variant in the gene called C9orf72 that predisposes him to develop this neurodegenerative disease, and he talks about his experience getting genetic testing and decision with his wife to undergo IVF and pre-implantation genetic diagnosis to ensure that their child did not inherit the genetic variant. Daniel joins Patrick to discuss the lack of availability of genetic testing in ALS, how to make genetic testing more accessible, breaking down stigmas in hereditary disease, and his work with the non-profit 'I AM ALS’. Patrick also mentions the upcoming Festival Genomics with over 100 great speakers. You can find out more here: https://www.festivalofgenomics.com/

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.01.362269v1?rss=1 Authors: The NeuroLINCS Consortium,, Ornelas, L., Gomez, E., Panther, L., Frank, A., Lei, S., Mandefro, B., Banuelos, M. G., Shelley, B., Kaye, J. A., Lima, L., Wyman, S., Lim, R. G., Wu, J., Stocksdale, J., Casale, M., Dardov, V., Matlock, A., Venkatraman, V., Holewenski, R., Milani, P., Adam, M., Wassie, B. T., Cheng, A., Coyne, A. N., Daigle, J. G., Li, J., Yang, S., Cox, V., Wilhelm, M., Lloyd, T. E., Hayes, L., Pham, J., Escalante-Chong, R., Lenail, A., Sachs, K., Patel-Murray, N. L., Ramamoorthy, D., Thompson, T. G., NYGC ALS Consortium,, Finkbeiner, S., Fraenkel, E., Rothstein, J. D., Sareen Abstract: Neurodegenerative diseases present a challenge for systems biology, due to the lack of reliable animal models and the difficulties in obtaining samples from patients at early stages of disease, when interventions might be most effective. Studying induced pluripotent stem cell (iPSC)-derived neurons could overcome these challenges and dramatically accelerate and broaden therapeutic strategies. Here we undertook a network-based multi-omic characterization of iPSC-derived motor neurons from ALS patients carrying genetically dominant hexanucleotide expansions in C9orf72 to gain a deeper understanding of the relationship between DNA, RNA, epigenetics and protein in the same pool of tissue. ALS motor neurons showed the expected C9orf72-related alterations to specific nucleoporins and production of dipeptide repeats. RNA-seq, ATAC-seq and data-independent acquisition mass-spectrometry (DIA-MS) proteomics were then performed on the same motor neuron cultures. Using integrative computational methods that combined all of the omics, we discovered a number of novel dysregulated pathways including biological adhesion and extracellular matrix organization and disruption in other expected pathways such as RNA splicing and nuclear transport. We tested the relevance of these pathways in vivo in a C9orf72 Drosophila model, analyzing the data to determine which pathways were causing disease phenotypes and which were compensatory. We also confirmed that some pathways are altered in late-stage neurodegeneration by analyzing human postmortem C9 cervical spine data. To validate that these key pathways were integral to the C9 signature, we prepared a separate set of C9orf72 and control motor neuron cultures using a different differentiation protocol and applied the same methods. As expected, there were major overall differences between the differentiation protocols, especially at the level of in individual omics data. However, a number of the core dysregulated pathways remained significant using the integrated multiomic analysis. This new method of analyzing patient specific neural cultures allows the generation of disease-related hypotheses with a small number of patient lines which can be tested in larger cohorts of patients. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.14.338566v1?rss=1 Authors: Shiota, T., Nagata, R., Kikuchi, S., Nanaura, H., Matsubayashi, M., Nakanishi, M., Kobashigawa, S., Nagayama, K., Sugie, K., Yamashiro, Y., Mori, E. Abstract: Amyotrophic lateral sclerosis (ALS) is an irreversible neurodegenerative disease caused by the degeneration of motor neurons, and cytoskeletal instability is considered to be involved in neurodegeneration. A hexanucleotide repeat expansion of the C9orf72, one of the most common causes of familial ALS, produces toxic proline:arginine (PR) poly-dipeptides. PR poly-dipeptides binds polymeric forms of low complexity sequences and intracellular puncta, thereby altering intermediate filaments (IFs). However, how PR poly-dipeptides affect the cytoskeleton, including IFs, microtubules and actin filaments, remains unknown. Here we performed a synthetic PR poly-dipeptide treatment on mammalian cells and investigated how it affects morphology of cytoskeleton and cell behaviors. We observed that PR poly-dipeptide treatment induce the degradation of vimentin bundles at perinucleus and dissociation of {beta}-tubulin network. PR poly-dipeptides also lead to alteration of actin filaments toward to cell contours and strength cortical actin filaments via activation of ERM (ezrin/radixin/moesin) proteins. In addition, we found that PR poly-dipeptides promote phosphorylation of paxillin and recruitment of vinculin on focal adhesions, which lead to maturation of focal adhesions. Finally, we evaluated the effects of PR poly-dipeptides on mechanical property and stress response. Interestingly, treatment of PR poly-dipeptides increased the elasticity of the cell surface, leading to maladaptive response to cyclic stretch. These results suggest that PR poly-dipeptides cause mechanically sensitive structural reorganization and disrupt the cytoskeleton architecture. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.14.297036v1?rss=1 Authors: Frottin, F., Perez-Berlanga, M., Hartl, F.-U., Hipp, M. S. Abstract: The most frequent genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia is a G4C2 repeat expansion in the C9orf72 gene. This expansion gives rise to translation of aggregating dipeptide repeat (DPR) proteins, including poly-GA as the most abundant species. However, gain of toxic function effects have been attributed to either the DPRs or the pathological G4C2 RNA. Here we analyzed in a cellular model the relative toxicity of DPRs and RNA. Cytoplasmic poly-GA aggregates, generated in the absence of G4C2 RNA, interfered with nucleocytoplasmic protein transport, but had little effect on cell viability. In contrast, nuclear poly-GA was more toxic, impairing nucleolar protein quality control and protein biosynthesis. Production of the G4C2 RNA strongly reduced viability independent of DPR translation and caused pronounced inhibition of nuclear mRNA export and protein biogenesis. Thus, while the toxic effects of G4C2 RNA predominate, DPRs exert additive effects that may contribute to pathology. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.15.297259v1?rss=1 Authors: Riemslagh, F. W., van der Toorn, E., Verhagen, R. F. M., Maas, A., Bosman, L. W., Hukema, R. K., Willemsen, R. Abstract: The hexanucleotide G4C2 repeat expansion in the first intron of the C9ORF72 gene explains the majority of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) cases. Numerous studies have indicated the toxicity of dipeptide repeats (DPRs) which are produced via repeat-associated non-AUG (RAN) translation from the repeat expansion and accumulate in the brain of C9FTD/ALS patients. Mouse models expressing the human C9ORF72 repeat and/or DPRs show variable pathological, functional and behavioral characteristics of FTD and ALS. Here, we report a new Tet-on inducible mouse model that expresses 36x pure G4C2 repeats with 100bp upstream and downstream human flanking regions. Brain specific expression causes the formation of sporadic sense DPRs aggregates upon 6 months dox induction but no apparent neurodegeneration. Expression in the rest of the body evokes abundant sense DPRs in multiple organs, leading to weight loss, neuromuscular junction disruption, myopathy and a locomotor phenotype within the time frame of four weeks. We did not observe any RNA foci or pTDP-43 pathology. Accumulation of DPRs and the myopathy phenotype could be prevented when 36x G4C2 repeat expression was stopped after 1 week. After 2 weeks of expression, the phenotype could not be reversed, even though DPR levels were reduced. In conclusion, expression of 36x pure G4C2 repeats including 100bp human flanking regions is sufficient for RAN translation of sense DPRs and evokes a functional locomotor phenotype. Our inducible mouse model highlights the importance of early diagnosis and treatment for C9FTD/ALS patients. 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/2020.08.30.274597v1?rss=1 Authors: Loveland, A. B., Svidritskiy, E., Susorov, D., Lee, S., Park, A., Demo, G., Gao, F.-B., Korostelev, A. A. Abstract: Toxic dipeptide repeat (DPR) proteins are produced from expanded G4C2 hexanucleotide repeats in the C9ORF72 gene, which cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two DPR proteins, poly-PR and poly-GR, repress cellular translation but the molecular mechanism remains unknown. Here we show that poly-PR and poly-GR of [≥] 20 repeats inhibit the ribosome's peptidyl-transferase activity at nanomolar concentrations, comparable to specific translation inhibitors. High-resolution cryo-EM structures reveal that poly-PR and poly-GR block the polypeptide tunnel of the ribosome, extending into the peptidyl-transferase center. Consistent with these findings, the macrolide erythromycin, which binds in the tunnel, competes with the DPR proteins and restores peptidyl-transferase activity. Our results demonstrate that strong and specific binding of poly-PR and poly-GR in the ribosomal tunnel blocks translation, revealing the structural basis of their toxicity in C9ORF72-ALS/FTD. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.13.150029v1?rss=1 Authors: Sonobe, Y., Aburas, J., Islam, P., Gendron, T. F., Brown, A. E. X., Roos, R. P., Kratsios, P. Abstract: A hexanucleotide repeat expansion GGGGCC in the noncoding region of C9orf72 is the most common cause of inherited amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Potentially toxic dipeptide repeats (DPRs) are synthesized from the GGGGCC sequence via repeat associated non-AUG (RAN) translation. We developed C. elegans models that express, either ubiquitously or exclusively in neurons, a transgene with 75 GGGGCC repeats flanked by intronic C9orf72 sequence. The worms generate DPRs (poly-glycine-alanine [poly-GA], poly-glycine-proline [poly-GP]) and display neurodegeneration, locomotor and lifespan defects. Mutation of a non-canonical translation-initiating codon (CUG) upstream of the repeats blocked poly-GA production and ameliorated disease, suggesting poly-GA is pathogenic. Importantly, eukaryotic translation initiation factor 2D (eif-2D/eIF2D) was necessary for RAN translation. Genetic removal of eif-2D increased lifespan in both C. elegans models. In vitro findings in human cells demonstrated a conserved role for eif-2D/eIF2D in RAN translation that could be exploited for ALS and FTD therapy. 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/2020.05.20.106260v1?rss=1 Authors: Premasiri, A. S., Gill, A. L., Vieira, F. G. Abstract: The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a repeat expansion mutation in the C9orf72 gene. Repeat-associated non-AUG (RAN) translation of this expansion produces five species of dipeptide repeat proteins (DRPs). The arginine containing DRPs, polyGR and polyPR, are consistently reported to be the most toxic. Here, we uncover Type I protein arginine methyltransferase (PRMT) inhibitors as possible therapeutics for polyGR- and polyPR- related toxicity. Furthermore, we reveal data that suggest that asymmetric dimethylation (ADMe) of polyGR is a determining factor in its pathogenesis. Copy rights belong to original authors. Visit the link for more info

In this episode of the Endpoints, Dr. Fernando Vieira explains what we know so far about C9ORF72, a gene which has been implicated in up to 40% of cases of familial ALS. C9ORF72was discovered to be a cause of ALS 8 years ago but there is still a lot for researchers to learn about its unique characteristics. Dr. Vieira talks about some of the hurdles to overcome and what researchers are doing right now to try to address this mutation. You can access all episodes of the Endpoints Podcast for free by visiting www.als.net/endpoints and registering. Support the show.

Dr. Guy Rouleau discusses the main takeaways from his Neurology: Genetics paper on how the somatic expansion of the C9orf72 Hexanucleotide repeat does not occur in ALS spinal cord tissues.

Nesse episódio do GENE Highlights, gravado durante a 49ª Jornada Paulista de Radiologia, realizada em maio de 2019, em São Paulo, o Dr. Felipe Pacheco entrevista o Dr. Victor Hugo Marussi, que fala sobre as aplicações do imaging genomics em demências. Os episódios do Highlights produzidos durante a 49ª Jornada Paulista de Radiologia, serão publicados às segundas-feiras, no mês de maio até o mês de julho. Serão oito episódios que abordam os assuntos mais relevantes da área da radiologia. A produção conta com o apoio dos grupos de estudos da SPR. A live mencionada pelo Dr. Felipe pode ser consultada no link abaixo: https://www.facebook.com/sociedadepaulistaderadiologia/videos/337162283669582/ Abaixo, seguem os artigos de referência dessa entrevista: Harper L, Barkhof F, Scheltens P, Schott JM, Fox NC. An algorithmic approach to structural imaging in dementia. (2014) Journal of neurology, neurosurgery, and psychiatry. 85 (6): 692-8 - https://www.ncbi.nlm.nih.gov/pubmed/24133287 Murray AD. Imaging approaches for dementia. (2012) AJNR. American journal of neuroradiology. 33 (10): 1836-44 https://www.ncbi.nlm.nih.gov/pubmed/22135130 Olszewska DA, Lonergan R, Fallon EM, Lynch T. Genetics of Frontotemporal Dementia. (2016) Current neurology and neuroscience reports. 16 (12): 107. https://www.ncbi.nlm.nih.gov/pubmed/27878525 Elahi FM, Miller BL. A clinicopathological approach to the diagnosis of dementia. (2017) Nature reviews. Neurology. 13 (8): 457-476. https://www.ncbi.nlm.nih.gov/pubmed/28708131 Conklin J, Silver FL, Mikulis DJ, Mandell DM. Are acute infarcts the cause of leukoaraiosis? Brain mapping for 16 consecutive weeks. (2014) Annals of neurology. 76 (6): 899-904. https://www.ncbi.nlm.nih.gov/pubmed/25283088 Landin-Romero R, Tan R, Hodges JR, Kumfor F. An update on semantic dementia: genetics, imaging, and pathology. (2016) Alzheimer's research & therapy. 8 (1): 52. https://www.ncbi.nlm.nih.gov/pubmed/27915998 Hansen TP, Cain J, Thomas O, Jackson A. Dilated perivascular spaces in the Basal Ganglia are a biomarker of small-vessel disease in a very elderly population with dementia. (2015) AJNR. American journal of neuroradiology. 36 (5): 893-8. https://www.ncbi.nlm.nih.gov/pubmed/25698626 Laveskog A, Wang R, Bronge L, Wahlund LO, Qiu C. Perivascular Spaces in Old Age: Assessment, Distribution, and Correlation with White Matter Hyperintensities. (2018) AJNR. American journal of neuroradiology. 39 (1): 70-76. https://www.ncbi.nlm.nih.gov/pubmed/29170267 Scahill RI, Ridgway GR, Bartlett JW, Barnes J, Ryan NS, Mead S, Beck J, Clarkson MJ, Crutch SJ, Schott JM, Ourselin S, Warren JD, Hardy J, Rossor MN, Fox NC. Genetic influences on atrophy patterns in familial Alzheimer's disease: a comparison of APP and PSEN1 mutations. (2013) Journal of Alzheimer's disease : JAD. 35 (1): 199-212. https://www.ncbi.nlm.nih.gov/pubmed/23380992 Whitwell JL, Weigand SD, Boeve BF, Senjem ML, Gunter JL, DeJesus-Hernandez M, Rutherford NJ, Baker M, Knopman DS, Wszolek ZK, Parisi JE, Dickson DW, Petersen RC, Rademakers R, Jack CR, Josephs KA. Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics. (2012) Brain : a journal of neurology. 135 (Pt 3): 794-806. https://www.ncbi.nlm.nih.gov/pubmed/22366795 Rohrer JD. Structural brain imaging in frontotemporal dementia. (2012) Biochimica et biophysica acta. 1822 (3): 325-32. https://www.ncbi.nlm.nih.gov/pubmed/21839829 López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. (2013) Cell. 153 (6): 1194-217. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836174/

Both patient and editor's choices are discussed in this monthly episode of the JNNP podcast. The clinical care of patients with Guillain-Barré syndrome (GBS) can often be complex; a disease with a highly variable clinical course. Professor Bart Jacobs, from the Department of Neurology at Erasmus Medical Centre (Rotterdam) provides an overview of some of the dilemmas that may arise when treating patients with GBS. The full article: http://jnnp.bmj.com/content/88/4/346. In the second part of this podcast: The C9orf72 repeat expansion is reported to have a negative impact on prognosis in amyotrophic lateral sclerosis (ALS). Until now, researchers have not been able to examine the relationship between C9orf72 and factors such as age, site of onset or gender. Dr James Rooney discusses how he and colleagues examined the prognostic impact of the C9orf72 repeat expansion in more detail. The full article is available here: http://jnnp.bmj.com/content/88/4/281.1.

Thu, 14 Apr 2016 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/19405/ https://edoc.ub.uni-muenchen.de/19405/1/May_Stephanie.pdf May, Stephanie

Interview with Steve Vucic, PhD, author of Cortical Function in Asymptomatic Carriers and Patients With C9orf72 Amyotrophic Lateral Sclerosis, and Brian J. Wainger, MD, PhD, author of Cortical Hyperexcitability in Amyotrophic Lateral Sclerosis: C9orf72 Repeats

Steven Goodrick talks to Jonathan Rohrer about the latest research in C9orf72 expansions.

Stuart Pickering-Brown, Professor of Neurogenetics and MRC Senior Research Fellow, Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester - UK speaks on "Cellular modeling of the C9orf72 repeat expansion - RNA Metabolism: Changing Paradigms in Neurodegeneration” This seminar has been recorded at Area Science Park Trieste by ICGEB Trieste

Robert Baloh, Cedars-Sinai, Director, Neuromuscular Medicine, ALS Program, Neurodegenerative Diseases Laboratory, Advanced Health Sciences Pavilion Los Angeles - USA speaks on "Cellular and animal models to understand C9ORF72 repeat expansion in ALS and FTLD - RNA Metabolism: Changing Paradigms in Neurodegeneration” This seminar has been recorded at Area Science Park Trieste by ICGEB Trieste

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

Clotilde Lagier-Tourenne, Assistant Investigator, Ludwig Institute for Cancer Research, Assistant Professor, Department of Neurosciences, University of California, San Diego, La Jolla - USA - speaks on "Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration - 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

Guest We interview Dr. Asif Maroof, a post-doctoral fellow in the lab of Dr. Kevin Eggan at the Harvard Stem Cell Institute to talk about his latest paper in Nature Neuroscience describing a gene implicated…

Jeff Rothstein MD PhD, director of the Packard Center for ALS Research at Johns Hopkins University School of Medicine, talks C9ORF72 and potential treatments for this form of ALS going forward. Read more: http://blogs.als.net/post/2012/10/29/ALS-dressed-to-the-C9s.aspx

Interview with Leonel T. Takada, MD, author of Frontotemporal Dementia in a Brazilian Kindred With the C9orf72 Mutation

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.10.036400v1?rss=1 Authors: Swartz, E. W., Shintani, G., Wan, J., Maffei, J. S., Wang, S. H., Miller, B. L., Havton, L. A., Coppola, G. Abstract: The failure of the neuromuscular junction (NMJ) is a key component of degenerative neuromuscular disease, yet how NMJs degenerate in disease is unclear. Human induced pluripotent stem cells (hiPSCs) offer the ability to model disease via differentiation toward affected cell types, however, the re-creation of an in vitro neuromuscular system has proven challenging. Here we present a scalable, all-hiPSC-derived co-culture system composed of independently derived spinal motor neurons (MNs) and skeletal myotubes (sKM). In a model of C9orf72-associated disease, co-cultures form functional NMJs that can be manipulated through optical stimulation, eliciting muscle contraction and measurable calcium flux in innervated sKM. Furthermore, co-cultures grown on multi-electrode arrays (MEAs) permit the pharmacological interrogation of neuromuscular physiology. Utilization of this co-culture model as a tunable, patient-derived system may offer significant insights into NMJ formation, maturation, repair, or pathogenic mechanisms that underlie NMJ dysfunction in disease. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.15.040394v1?rss=1 Authors: Pal, A., Kretner, B., Abo-Rady, M., Glass, H., Naumann, M., Japtok, J., Kreiter, N., Boeckers, T. M., Sterneckert, J., Hermann, A. Abstract: Intronic hexanucleotide repeat expansions (HREs) in C9ORF72 are the most frequent genetic cause of amyotrophic lateral sclerosis (ALS), a devastating, incurable motoneuron (MN) disease. The mechanism by which HREs trigger pathogenesis remains elusive. The discovery of repeat-associated non-ATG (RAN) translation of dipeptide repeat proteins (DPRs) from HREs along with reduced exonic C9ORF72 expression suggests gain of toxic functions (GOF) through DPRs versus loss of C9ORF72 functions (LOF). Through multiparametric HC live profiling in spinal MNs from induced pluripotent stem cells (iPSCs) and comparison to mutant FUS and TDP43, we show that HRE C9ORF72 caused a distinct, later spatiotemporal appearance of mainly proximal axonal organelle motility deficits concomitant to augmented DNA strand breaks (DSBs), DPRs and apoptosis. We show that both GOF and LOF were necessary to yield the overall C9ORF72 pathology. Finally, C9ORF72 LOF was sufficient, albeit to a smaller extent, to induce proximal axonal trafficking deficits and increased DSBs. Copy rights belong to original authors. Visit the link for more info