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1. Heterozygous knockout of Synaptotagmin13 phenocopies ALS features and TP53 activation in human motor neurons

Author

Johannes Lehmann, Amr Aly, Christina Steffke, Luca Fabbio, Valentin Mayer, Natalie Dikwella, Kareen Halablab, Francesco Roselli, Simone Seiffert, Tobias M. Boeckers, David Brenner, Edor Kabashi, Medhanie Mulaw, Ritchie Ho, and Alberto Catanese

Subjects
Cytology, QH573-671
Abstract

Abstract Spinal motor neurons (MNs) represent a highly vulnerable cellular population, which is affected in fatal neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). In this study, we show that the heterozygous loss of SYT13 is sufficient to trigger a neurodegenerative phenotype resembling those observed in ALS and SMA. SYT13+/− hiPSC-derived MNs displayed a progressive manifestation of typical neurodegenerative hallmarks such as loss of synaptic contacts and accumulation of aberrant aggregates. Moreover, analysis of the SYT13+/− transcriptome revealed a significant impairment in biological mechanisms involved in motoneuron specification and spinal cord differentiation. This transcriptional portrait also strikingly correlated with ALS signatures, displaying a significant convergence toward the expression of pro-apoptotic and pro-inflammatory genes, which are controlled by the transcription factor TP53. Our data show for the first time that the heterozygous loss of a single member of the synaptotagmin family, SYT13, is sufficient to trigger a series of abnormal alterations leading to MN sufferance, thus revealing novel insights into the selective vulnerability of this cell population.

Published
2024
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2. TANGO2-related rhabdomyolysis symptoms are associated with abnormal autophagy functioning

Author

Hortense de Calbiac, Sebastian Montealegre, Marjolène Straube, Solène Renault, Hugo Debruge, Loïc Chentout, Sorana Ciura, Apolline Imbard, Edouard Le Guillou, Anca Marian, Nicolas Goudin, Laure Caccavelli, Sylvie Fabrega, Arnaud Hubas, Peter van Endert, Nicolas Dupont, Julien Diana, Edor Kabashi, and Pascale de Lonlay

Subjects
Autophagy, calpeptin, myoblasts, rhabdomyolysis, TANGO2, zebrafish, Cytology, QH573-671
Abstract

ABSTRACTPatients with pathogenic variants in the TANGO2 gene suffer from severe and recurrent rhabdomyolysis episodes precipitated by fasting. Autophagy functioning was analyzed in vitro, in primary skeletal myoblasts from TANGO2 patients, in basal and fasting conditions, and TANGO2 mutations were associated with reduced LC3-II levels upon starvation. In zebrafish larvae, tango2 inhibition induced locomotor defects which were exacerbated by exposure to atorvastatin, a compound known to cause rhabdomyolysis. Importantly, rhabdomyolysis features of tango2 knockdown were associated with autophagy and mitophagy defects in zebrafish. Calpeptin treatment was sufficient to rescue the locomotor properties thanks to its beneficial effect on autophagy functioning in zebrafish and to improve LC3-II levels in starved primary muscle cells of TANGO2 patients. Overall, we demonstrated that TANGO2 plays an important role in autophagy thus giving rise to new therapeutic perspectives in the prevention of RM life-threatening episodes.

Published
2024
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3. Author Correction: Integrative genetic analysis illuminates ALS heritability and identifies risk genes

Author

Salim Megat, Natalia Mora, Jason Sanogo, Olga Roman, Alberto Catanese, Najwa Ouali Alami, Axel Freischmidt, Xhuljana Mingaj, Hortense De Calbiac, François Muratet, Sylvie Dirrig-Grosch, Stéphane Dieterle, Nick Van Bakel, Kathrin Müller, Kirsten Sieverding, Jochen Weishaupt, Peter Munch Andersen, Markus Weber, Christoph Neuwirth, Markus Margelisch, Andreas Sommacal, Kristel R. Van Eijk, Jan H. Veldink, Project Mine Als Sequencing Consortium, Géraldine Lautrette, Philippe Couratier, Agnès Camuzat, Isabelle Le Ber, Maurizio Grassano, Adriano Chio, Tobias Boeckers, Albert C. Ludolph, Francesco Roselli, Deniz Yilmazer-Hanke, Stéphanie Millecamps, Edor Kabashi, Erik Storkebaum, Chantal Sellier, and Luc Dupuis

Subjects
Science
Published
2023
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4. Overexpression of Toxic Poly(Glycine-Alanine) Aggregates in Primary Neuronal Cultures Induces Time-Dependent Autophagic and Synaptic Alterations but Subtle Activity Impairments

Author

Christina Steffke, Shreya Agarwal, Edor Kabashi, and Alberto Catanese

Subjects
C9orf72, ALS, poly(GA), autophagy, synapse, MEA, Cytology, QH573-671
Abstract

The pathogenic expansion of the intronic GGGGCC hexanucleotide located in the non-coding region of the C9orf72 gene represents the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This mutation leads to the accumulation of toxic RNA foci and dipeptide repeats (DPRs), as well as reduced levels of the C9orf72 protein. Thus, both gain and loss of function are coexisting pathogenic aspects linked to C9orf72-ALS/FTD. Synaptic alterations have been largely described in C9orf72 models, but it is still not clear which aspect of the pathology mostly contributes to these impairments. To address this question, we investigated the dynamic changes occurring over time at the synapse upon accumulation of poly(GA), the most abundant DPR. Overexpression of this toxic form induced a drastic loss of synaptic proteins in primary neuron cultures, anticipating autophagic defects. Surprisingly, the dramatic impairment characterizing the synaptic proteome was not fully matched by changes in network properties. In fact, high-density multi-electrode array analysis highlighted only minor reductions in the spike number and firing rate of poly(GA) neurons. Our data show that the toxic gain of function linked to C9orf72 affects the synaptic proteome but exerts only minor effects on the network activity.

Published
2024
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5. Microglia Mitigate Neuronal Activation in a Zebrafish Model of Dravet Syndrome

Author

Alexandre Brenet, Julie Somkhit, Zsolt Csaba, Sorana Ciura, Edor Kabashi, Constantin Yanicostas, and Nadia Soussi-Yanicostas

Subjects
microglia, epilepsy, seizure, calcium imaging, zebrafish, seizures, Cytology, QH573-671
Abstract

It has been known for a long time that epileptic seizures provoke brain neuroinflammation involving the activation of microglial cells. However, the role of these cells in this disease context and the consequences of their inflammatory activation on subsequent neuron network activity remain poorly understood so far. To fill this gap of knowledge and gain a better understanding of the role of microglia in the pathophysiology of epilepsy, we used an established zebrafish Dravet syndrome epilepsy model based on Scn1Lab sodium channel loss-of-function, combined with live microglia and neuronal Ca2+ imaging, local field potential (LFP) recording, and genetic microglia ablation. Data showed that microglial cells in scn1Lab-deficient larvae experiencing epileptiform seizures displayed morphological and biochemical changes characteristic of M1-like pro-inflammatory activation; i.e., reduced branching, amoeboid-like morphology, and marked increase in the number of microglia expressing pro-inflammatory cytokine Il1β. More importantly, LFP recording, Ca2+ imaging, and swimming behavior analysis showed that microglia-depleted scn1Lab-KD larvae displayed an increase in epileptiform seizure-like neuron activation when compared to that seen in scn1Lab-KD individuals with microglia. These findings strongly suggest that despite microglia activation and the synthesis of pro-inflammatory cytokines, these cells provide neuroprotective activities to epileptic neuronal networks, making these cells a promising therapeutic target in epilepsy.

Published
2024
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6. Integrative genetic analysis illuminates ALS heritability and identifies risk genes

Author

Salim Megat, Natalia Mora, Jason Sanogo, Olga Roman, Alberto Catanese, Najwa Ouali Alami, Axel Freischmidt, Xhuljana Mingaj, Hortense De Calbiac, François Muratet, Sylvie Dirrig-Grosch, Stéphane Dieterle, Nick Van Bakel, Kathrin Müller, Kirsten Sieverding, Jochen Weishaupt, Peter Munch Andersen, Markus Weber, Christoph Neuwirth, Markus Margelisch, Andreas Sommacal, Kristel R. Van Eijk, Jan H. Veldink, Project Mine Als Sequencing Consortium, Géraldine Lautrette, Philippe Couratier, Agnès Camuzat, Isabelle Le Ber, Maurizio Grassano, Adriano Chio, Tobias Boeckers, Albert C. Ludolph, Francesco Roselli, Deniz Yilmazer-Hanke, Stéphanie Millecamps, Edor Kabashi, Erik Storkebaum, Chantal Sellier, and Luc Dupuis

Subjects
Science
Abstract

Abstract Amyotrophic lateral sclerosis (ALS) has substantial heritability, in part shared with fronto-temporal dementia (FTD). We show that ALS heritability is enriched in splicing variants and in binding sites of 6 RNA-binding proteins including TDP-43 and FUS. A transcriptome wide association study (TWAS) identified 6 loci associated with ALS, including in NUP50 encoding for the nucleopore basket protein NUP50. Independently, rare variants in NUP50 were associated with ALS risk (P = 3.71.10−03; odds ratio = 3.29; 95%CI, 1.37 to 7.87) in a cohort of 9,390 ALS/FTD patients and 4,594 controls. Cells from one patient carrying a NUP50 frameshift mutation displayed a decreased level of NUP50. Loss of NUP50 leads to death of cultured neurons, and motor defects in Drosophila and zebrafish. Thus, our study identifies alterations in splicing in neurons as critical in ALS and provides genetic evidence linking nuclear pore defects to ALS.

Published
2023
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7. Functional characterisation of the amyotrophic lateral sclerosis risk locus GPX3/TNIP1

Author

Restuadi Restuadi, Frederik J. Steyn, Edor Kabashi, Shyuan T. Ngo, Fei-Fei Cheng, Marta F. Nabais, Mike J. Thompson, Ting Qi, Yang Wu, Anjali K. Henders, Leanne Wallace, Chris R. Bye, Bradley J. Turner, Laura Ziser, Susan Mathers, Pamela A. McCombe, Merrilee Needham, David Schultz, Matthew C. Kiernan, Wouter van Rheenen, Leonard H. van den Berg, Jan H. Veldink, Roel Ophoff, Alexander Gusev, Noah Zaitlen, Allan F. McRae, Robert D. Henderson, Naomi R. Wray, Jean Giacomotto, and Fleur C. Garton

Subjects
Motor neurone disease, MND, Genome-wide association study, Computational biology, Zebrafish, Neurodegenerative diseases, Medicine, Genetics, QH426-470
Abstract

Abstract Background Amyotrophic lateral sclerosis (ALS) is a complex, late-onset, neurodegenerative disease with a genetic contribution to disease liability. Genome-wide association studies (GWAS) have identified ten risk loci to date, including the TNIP1/GPX3 locus on chromosome five. Given association analysis data alone cannot determine the most plausible risk gene for this locus, we undertook a comprehensive suite of in silico, in vivo and in vitro studies to address this. Methods The Functional Mapping and Annotation (FUMA) pipeline and five tools (conditional and joint analysis (GCTA-COJO), Stratified Linkage Disequilibrium Score Regression (S-LDSC), Polygenic Priority Scoring (PoPS), Summary-based Mendelian Randomisation (SMR-HEIDI) and transcriptome-wide association study (TWAS) analyses) were used to perform bioinformatic integration of GWAS data (N cases = 20,806, N controls = 59,804) with ‘omics reference datasets including the blood (eQTLgen consortium N = 31,684) and brain (N = 2581). This was followed up by specific expression studies in ALS case-control cohorts (microarray N total = 942, protein N total = 300) and gene knockdown (KD) studies of human neuronal iPSC cells and zebrafish-morpholinos (MO). Results SMR analyses implicated both TNIP1 and GPX3 (p < 1.15 × 10−6), but there was no simple SNP/expression relationship. Integrating multiple datasets using PoPS supported GPX3 but not TNIP1. In vivo expression analyses from blood in ALS cases identified that lower GPX3 expression correlated with a more progressed disease (ALS functional rating score, p = 5.5 × 10−3, adjusted R 2 = 0.042, B effect = 27.4 ± 13.3 ng/ml/ALSFRS unit) with microarray and protein data suggesting lower expression with risk allele (recessive model p = 0.06, p = 0.02 respectively). Validation in vivo indicated gpx3 KD caused significant motor deficits in zebrafish-MO (mean difference vs. control ± 95% CI, vs. control, swim distance = 112 ± 28 mm, time = 1.29 ± 0.59 s, speed = 32.0 ± 2.53 mm/s, respectively, p for all

Published
2022
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8. Synaptic disruption and CREB‐regulated transcription are restored by K+ channel blockers in ALS

Author

Alberto Catanese, Sandeep Rajkumar, Daniel Sommer, Dennis Freisem, Alexander Wirth, Amr Aly, David Massa‐López, Andrea Olivieri, Federica Torelli, Valentin Ioannidis, Joanna Lipecka, Ida Chiara Guerrera, Daniel Zytnicki, Albert Ludolph, Edor Kabashi, Medhanie A Mulaw, Francesco Roselli, and Tobias M Böckers

Subjects
ALS, CREB, hiPSC, motoneuron, synapse, Medicine (General), R5-920, Genetics, QH426-470
Abstract

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, which is still missing effective therapeutic strategies. Although manipulation of neuronal excitability has been tested in murine and human ALS models, it is still under debate whether neuronal activity might represent a valid target for efficient therapies. In this study, we exploited a combination of transcriptomics, proteomics, optogenetics and pharmacological approaches to investigate the activity‐related pathological features of iPSC‐derived C9orf72‐mutant motoneurons (MN). We found that human ALSC9orf72 MN are characterized by accumulation of aberrant aggresomes, reduced expression of synaptic genes, loss of synaptic contacts and a dynamic “malactivation” of the transcription factor CREB. A similar phenotype was also found in TBK1‐mutant MN and upon overexpression of poly(GA) aggregates in primary neurons, indicating a strong convergence of pathological phenotypes on synaptic dysregulation. Notably, these alterations, along with neuronal survival, could be rescued by treating ALS‐related neurons with the K+ channel blockers Apamin and XE991, which, respectively, target the SK and the Kv7 channels. Thus, our study shows that restoring the activity‐dependent transcriptional programme and synaptic composition exerts a neuroprotective effect on ALS disease progression.

Published
2021
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9. Association of Rare Genetic Variants in Opioid Receptors with Tourette Syndrome

Author

Christel Depienne, Sorana Ciura, Oriane Trouillard, Delphine Bouteiller, Elsa Leitã;o, Caroline Nava, Boris Keren, Yannick Marie, Justine Guegan, Sylvie Forlani, Alexis Brice, Mathieu Anheim, Yves Agid, Paul Krack, Philippe Damier, François Viallet, Jean-Luc Houeto, Franck Durif, Marie Vidailhet, Yulia Worbe, Emmanuel Roze, Edor Kabashi, and Andreas Hartmann

Subjects
tourette syndrome, gene, variant, susceptibility factor, opioid receptor, zebrafish, oprk1, Diseases of the musculoskeletal system, RC925-935, Neurology. Diseases of the nervous system, RC346-429
Abstract

Background: Genes involved in Tourette syndrome (TS) remain largely unknown. We aimed to identify genetic factors contributing to TS in a French cohort of 120 individuals using a combination of hypothesis-driven and exome-sequencing approaches. Methods: We first sequenced exons of SLITRK1-6 and HDC in the TS cohort and subsequently sequenced the exome of 12 individuals harboring rare variants in these genes to find additional rare variants contributing to the disorder under the hypothesis of oligogenic inheritance. We further screened three candidate genes (OPRK1, PCDH10, and NTSR2) preferentially expressed in the basal ganglia, and three additional genes involved in neurotensin and opioid signaling (OPRM1, NTS, and NTSR1), and compared variant frequencies in TS patients and 788 matched control individuals. We also investigated the impact of altering the expression of Oprk1 in zebrafish. Results: Thirteen ultrarare missense variants of SLITRK1-6 and HDC were identified in 12 patients. Exome sequencing in these patients revealed rare possibly deleterious variants in 3,041 genes, 54 of which were preferentially expressed in the basal ganglia. Comparison of variant frequencies altering selected candidate genes in TS and control individuals revealed an excess of potentially disrupting variants in OPRK1, encoding the opioid kappa receptor, in TS patients. Accordingly, we show that downregulation of the Oprk1 orthologue in zebrafish induces a hyperkinetic phenotype in early development. Discussion: These results support a heterogeneous and complex genetic etiology of TS, possibly involving rare variants altering the opioid pathway in some individuals, which could represent a novel therapeutic target in this disorder.

Published
2019
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10. Functional characterization of a FUS mutant zebrafish line as a novel genetic model for ALS

Author

Annis-Rayan Bourefis, Maria-Letizia Campanari, Valerie Buee-Scherrer, and Edor Kabashi

Subjects
Amyotrophic lateral sclerosis (ALS), Motor neuron, Neuromuscular junction, Zebrafish, FUS, Tau, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Mutations in Fused in sarcoma (FUS), an RNA-binding protein, are known to cause Amyotrophic Lateral Sclerosis (ALS). However, molecular mechanisms due to loss of FUS function remain unclear and controversial. Here, we report the characterization and phenotypic analysis of a deletion mutant of the unique FUS orthologue in zebrafish where Fus protein levels are depleted. The homozygous mutants displayed a reduced lifespan as well as impaired motor abilities associated with specific cellular deficits, including decreased motor neurons length and neuromuscular junctions (NMJ) fragmentation. Furthermore, we demonstrate that these cellular impairments are linked to the misregulation of mRNA expression of acetylcholine receptor (AChR) subunits and histone deacetylase 4, markers of denervation and reinnervation processes observed in ALS patients. In addition, fus loss of function alters tau transcripts favoring the expression of small tau isoforms. Overall, this new animal model extends our knowledge on FUS and supports the relevance of FUS loss of function in ALS physiopathology.

Published
2020
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11. Freezing activity brief data from a new FUS mutant zebrafish line

Author

Maria-Letizia Campanari, Annis-Rayan Bourefis, Valerie Buee-Scherrer, and Edor Kabashi

Subjects
Zebrafish (Danio Rerio), FUS KO model, Visual stimulation with the automatized viewpoint zebrabox system, Freezing response, Behaviour, Computer applications to medicine. Medical informatics, R858-859.7, Science (General), Q1-390
Abstract

The data presented in this paper are related to the research article “Functional characterization of a FUS mutant zebrafish line as a novel genetic model for ALS”. In this model the lack of fus causes reduced lifespan as well as impaired motor abilities associated with a decrease of motor neurons axons lenght and an increase of neuromuscular junctions fragmentation.Data in this article describes the global locomotor activity data at 3, 4 and 5 days post fertilization in WT, fus heterozygous (fus+/−) and fus homozygous (fus−/−) zebrafish embryos as a response to visual light stimulation, with particular attention on the freezing respose.

Published
2020
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12. Diagnostic Challenge and Neuromuscular Junction Contribution to ALS Pathogenesis

Author

Maria-Letizia Campanari, Annis-Rayan Bourefis, and Edor Kabashi

Subjects
amyotrophic lateral sclerosis (ALS), axonopathy, neuromuscular junction (NMJ), dying back hypothesis, ALS-mimic diseases, Neurology. Diseases of the nervous system, RC346-429
Abstract

Amyotrophic lateral sclerosis (ALS) represents the major adult-onset motor neuron disease. Both human and animal studies reveal the critical implication of muscle and neuromuscular junctions (NMJs) in the initial phase of this disease. Despite the common efforts, ALS diagnosis remains particularly challenging since many other disorders can overlap yielding similar clinical phenotypic features. A combination of further research on the NMJ parameters that are specific for this disease and laboratory tests are crucial for the early determination of specific changes in the muscle, as well as in motor neuron and the prediction of ALS progression. Also, it could provide a powerful tool in the discrimination of particular ALS and ALS-mimic cases and increase the efficacy of therapeutic treatments.

Published
2019
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13. Transcriptomic Analysis of Zebrafish TDP-43 Transgenic Lines

Author

Alexandra Lissouba, Meijiang Liao, Edor Kabashi, and Pierre Drapeau

Subjects
amyotrophic lateral sclerosis, ALS, zebrafish, TDP-43, TARDBP, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Amyotrophic lateral sclerosis (ALS) is a late-onset progressive neurodegenerative disorder that affects both upper and lower motor neurons, leading to muscle atrophy with spasticity and eventual death in 3–5 years after the disease onset. More than 50 mutations linked to ALS have been found in the gene TARDBP, encoding the protein TDP-43 that is the predominant component of neuronal inclusions in ALS. TDP-43 is an RNA binding protein with glycine-rich domains that binds to more than 6,000 RNAs in the human brain. However, ALS-related mutations do not appear to affect the function of these genes, indicating that a toxic gain-of-function may occur. We generated transgenic zebrafish lines expressing human TDP-43, either the wild-type form or the ALS-causative G348C mutation identified in a subset of ALS patients, with the transgene expression driven by an inducible heat shock promoter in order to bypass a potential early mortality. The expression of the mutant but not the wild-type human TDP-43 in zebrafish embryos induced a reduction of the locomotor activity in response to touch compared to controls and moderate axonopathy of the motor neurons of the spinal cord, with premature branching of the main axonal branch, recapitulating previous results obtained by mRNA injections. We used these lines to investigate transcriptomic changes due to the presence of mutant TDP-43 using RNA sequencing and have found 159 genes that are differentially expressed compared to control, with 67 genes up-regulated and 92 genes down-regulated. These transcriptomic changes are in line with recent transcriptomic data obtained in mouse models, indicating that these zebrafish transgenic lines are adequate to further study TDP-43-related ALS.

Published
2018
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14. TDP-43 Regulation of AChE Expression Can Mediate ALS-Like Phenotype in Zebrafish

Author

Maria-Letizia Campanari, Anca Marian, Sorana Ciura, and Edor Kabashi

Subjects
amyotrophic lateral sclerosis (ALS), TAR DNA-binding protein 43 (TDP-43), neuromuscular junction (NMJ), knockdown (KD), acetylcholinesterase (AChE), Cytology, QH573-671
Abstract

The “distal axonopathy” hypothesis in amyotrophic lateral sclerosis (ALS) proposes that pathological changes occur at the neuromuscular junction (NMJ) early in the disease. While acetylcholinesterase (AChE) plays an important role in the functionality of the NMJ, its potential role in ALS remains unexplored. Here, we identified AChE as a limiting factor regulating muscle/motor neuron connection in a vertebrate model of ALS. Knockdown of the TAR DNA-binding protein 43 (TDP-43) orthologue in zebrafish resulted in early defects of motor functions coupled with NMJ disassembly. We found that a partially depleted tdp-43 caused a decrease of ache expression. Importantly, human AChE overexpression reduced the phenotypic defects in the tdp-43 loss of function model, with amelioration of post- and pre-synaptic deficits at the NMJ. In conclusion, our results provide a better understanding of the role of TDP-43 in the NMJ organization and indicate AChE as a contributing factor in the pathology of ALS. In particular, it may be implicated in the early defects that characterize NMJs in this major neurodegenerative disorder.

Published
2021
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15. Functional Characterization of Neurofilament Light Splicing and Misbalance in Zebrafish

Author

Doris Lou Demy, Maria Letizia Campanari, Raphael Munoz-Ruiz, Heather D. Durham, Benoit J. Gentil, and Edor Kabashi

Subjects
amyotrophic lateral sclerosis (ALS), neurofilament light (NEFL), TDP-43, zebrafish, neurofilaments (NFs), Cytology, QH573-671
Abstract

Neurofilaments (NFs), a major cytoskeletal component of motor neurons, play a key role in the differentiation, establishment and maintenance of their morphology and mechanical strength. The de novo assembly of these neuronal intermediate filaments requires the presence of the neurofilament light subunit (NEFL), whose expression is reduced in motor neurons in amyotrophic lateral sclerosis (ALS). This study used zebrafish as a model to characterize the NEFL homologue neflb, which encodes two different isoforms via a splicing of the primary transcript (neflbE4 and neflbE3). In vivo imaging showed that neflb is crucial for proper neuronal development, and that disrupting the balance between its two isoforms specifically affects the NF assembly and motor axon growth, with resultant motor deficits. This equilibrium is also disrupted upon the partial depletion of TDP-43 (TAR DNA-binding protein 43), an RNA-binding protein encoded by the gene TARDBP that is mislocalized into cytoplasmic inclusions in ALS. The study supports the interaction of the NEFL expression and splicing with TDP-43 in a common pathway, both biologically and pathogenetically.

Published
2020
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16. Fishing for causes and cures of motor neuron disorders

Author

Shunmoogum A. Patten, Gary A. B. Armstrong, Alexandra Lissouba, Edor Kabashi, J. Alex Parker, and Pierre Drapeau

Subjects
ALS, HSP, SMA, Zebrafish, Drug discovery, Motor neuron disorders, Medicine, Pathology, RB1-214
Abstract

Motor neuron disorders (MNDs) are a clinically heterogeneous group of neurological diseases characterized by progressive degeneration of motor neurons, and share some common pathological pathways. Despite remarkable advances in our understanding of these diseases, no curative treatment for MNDs exists. To better understand the pathogenesis of MNDs and to help develop new treatments, the establishment of animal models that can be studied efficiently and thoroughly is paramount. The zebrafish (Danio rerio) is increasingly becoming a valuable model for studying human diseases and in screening for potential therapeutics. In this Review, we highlight recent progress in using zebrafish to study the pathology of the most common MNDs: spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP). These studies indicate the power of zebrafish as a model to study the consequences of disease-related genes, because zebrafish homologues of human genes have conserved functions with respect to the aetiology of MNDs. Zebrafish also complement other animal models for the study of pathological mechanisms of MNDs and are particularly advantageous for the screening of compounds with therapeutic potential. We present an overview of their potential usefulness in MND drug discovery, which is just beginning and holds much promise for future therapeutic development.

Published
2014
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17. Pharmacological reduction of ER stress protects against TDP-43 neuronal toxicity in vivo

Author

Alexandra Vaccaro, Shunmoogum A. Patten, Dina Aggad, Carl Julien, Claudia Maios, Edor Kabashi, Pierre Drapeau, and J. Alex Parker

Subjects
TDP-43, ALS, Genetic models, Small molecules, ER stress, Neurodegeneration, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

C. elegans and D. rerio expressing mutant TAR DNA Binding Protein 43 (TDP-43) are powerful in vivo animal models for the genetics and pharmacology of amyotrophic lateral sclerosis (ALS). Using these small-animal models of ALS, we previously identified methylene blue (MB) as a potent suppressor of TDP-43 toxicity. Consequently here we investigated how MB might exert its neuroprotective properties and found that it acts through reduction of the endoplasmic reticulum (ER) stress response. We tested other compounds known to be active in the ER unfolded protein response in worms and zebrafish expressing mutant human TDP-43 (mTDP-43). We identified three compounds: salubrinal, guanabenz and a new structurally related compound phenazine, which also reduced paralysis, neurodegeneration and oxidative stress in our mTDP-43 models. Using C. elegans genetics, we showed that all four compounds act as potent suppressors of mTDP-43 toxicity through reduction of the ER stress response. Interestingly, these compounds operate through different branches of the ER unfolded protein pathway to achieve a common neuroprotective action. Our results indicate that protein-folding homeostasis in the ER is an important target for therapeutic development in ALS and other TDP-43-related neurodegenerative diseases.

Published
2013
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18. Spatacsin and spastizin act in the same pathway required for proper spinal motor neuron axon outgrowth in zebrafish

Author

Elodie Martin, Constantin Yanicostas, Agnès Rastetter, Seyedeh Maryam Alavi Naini, Alissia Maouedj, Edor Kabashi, Sophie Rivaud-Péchoux, Alexis Brice, Giovanni Stevanin, and Nadia Soussi-Yanicostas

Subjects
Hereditary spastic paraplegia, SPG11, SPG15, Spatacsin, Spastizin, Zebrafish, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Hereditary spastic paraplegias (HSPs) are rare neurological conditions caused by degeneration of the long axons of the cerebrospinal tracts, leading to locomotor impairment and additional neurological symptoms. There are more than 40 different causative genes, 24 of which have been identified, including SPG11 and SPG15 mutated in complex clinical forms. Since the vast majority of the causative mutations lead to loss of function of the corresponding proteins, we made use of morpholino-oligonucleotide (MO)-mediated gene knock-down to generate zebrafish models of both SPG11 and SPG15 and determine how invalidation of the causative genes (zspg11 and zspg15) during development might contribute to the disease. Micro-injection of MOs targeting each gene caused locomotor impairment and abnormal branching of spinal cord motor neurons at the neuromuscular junction. More severe phenotypes with abnormal tail developments were also seen. Moreover, partial depletion of both proteins at sub-phenotypic levels resulted in the same phenotypes, suggesting for the first time, in vivo, a genetic interaction between these genes. In conclusion, the zebrafish orthologues of the SPG11 and SPG15 genes are important for proper development of the axons of spinal motor neurons and likely act in a common pathway to promote their proper path finding towards the neuromuscular junction.

Published
2012
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19. Methylene blue protects against TDP-43 and FUS neuronal toxicity in C. elegans and D. rerio.

Author

Alexandra Vaccaro, Shunmoogum A Patten, Sorana Ciura, Claudia Maios, Martine Therrien, Pierre Drapeau, Edor Kabashi, and J Alex Parker

Subjects
Medicine, Science
Abstract

The DNA/RNA-binding proteins TDP-43 and FUS are found in protein aggregates in a growing number of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and related dementia, but little is known about the neurotoxic mechanisms. We have generated Caenorhabditis elegans and zebrafish animal models expressing mutant human TDP-43 (A315T or G348C) or FUS (S57Δ or R521H) that reflect certain aspects of ALS including motor neuron degeneration, axonal deficits, and progressive paralysis. To explore the potential of our humanized transgenic C. elegans and zebrafish in identifying chemical suppressors of mutant TDP-43 and FUS neuronal toxicity, we tested three compounds with potential neuroprotective properties: lithium chloride, methylene blue and riluzole. We identified methylene blue as a potent suppressor of TDP-43 and FUS toxicity in both our models. Our results indicate that methylene blue can rescue toxic phenotypes associated with mutant TDP-43 and FUS including neuronal dysfunction and oxidative stress.

Published
2012
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20. FUS and TARDBP but not SOD1 interact in genetic models of amyotrophic lateral sclerosis.

Author

Edor Kabashi, Valérie Bercier, Alexandra Lissouba, Meijiang Liao, Edna Brustein, Guy A Rouleau, and Pierre Drapeau

Subjects
Genetics, QH426-470
Abstract

Mutations in the SOD1 and TARDBP genes have been commonly identified in Amyotrophic Lateral Sclerosis (ALS). Recently, mutations in the Fused in sarcoma gene (FUS) were identified in familial (FALS) ALS cases and sporadic (SALS) patients. Similarly to TDP-43 (coded by TARDBP gene), FUS is an RNA binding protein. Using the zebrafish (Danio rerio), we examined the consequences of expressing human wild-type (WT) FUS and three ALS-related mutations, as well as their interactions with TARDBP and SOD1. Knockdown of zebrafish Fus yielded a motor phenotype that could be rescued upon co-expression of wild-type human FUS. In contrast, the two most frequent ALS-related FUS mutations, R521H and R521C, unlike S57Δ, failed to rescue the knockdown phenotype, indicating loss of function. The R521H mutation caused a toxic gain of function when expressed alone, similar to the phenotype observed upon knockdown of zebrafish Fus. This phenotype was not aggravated by co-expression of both mutant human TARDBP (G348C) and FUS (R521H) or by knockdown of both zebrafish Tardbp and Fus, consistent with a common pathogenic mechanism. We also observed that WT FUS rescued the Tardbp knockdown phenotype, but not vice versa, suggesting that TARDBP acts upstream of FUS in this pathway. In addition we observed that WT SOD1 failed to rescue the phenotype observed upon overexpression of mutant TARDBP or FUS or upon knockdown of Tardbp or Fus; similarly, WT TARDBP or FUS also failed to rescue the phenotype induced by mutant SOD1 (G93A). Finally, overexpression of mutant SOD1 exacerbated the motor phenotype caused by overexpression of mutant FUS. Together our results indicate that TARDBP and FUS act in a pathogenic pathway that is independent of SOD1.

Published
2011
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21. Abnormal autophagy is a critical mechanism in TANGO2-related rhabdomyolysis

Author

Sebastian Montealegre, Hortense de Calbiac, Marjolène Straube, Hugo Debruge, Loïc Chentout, Sorana Ciura, Apolline Imbard, Edouard Le Guillou, Anca Marian, Nicolas Goudin, Laure Caccavelli, Sylvie Fabrega, Arnaud Hubas, Peter van Endert, Nicolas Dupont, Julien Diana, Edor Kabashi, and Pascale de Lonlay

Abstract

Patients with pathogenic variants in the TANGO2 gene suffer from severe and recurrent rhabdomyolysis (RM) episodes precipitated by fasting. Since starvation promotes autophagy induction, we wondered whether TANGO2-related muscle symptoms result from autophagy insufficiency to meet cellular demands in stress conditions. Autophagy functioning was analyzed in vitro, in primary skeletal muscle cells from TANGO2 patients in basal and fasting conditions. In addition, wce developed a tango2 morphant zebrafish model to assess the effect of tango2 knockdown (KD) on locomotor function and autophagy efficiency in vivo. We report that TANGO2 mutations are associated with decreased LC3-II levels upon starvation in primary muscle cells, but not in fibroblasts. In zebrafish larvae, tango2 knockdown induces locomotor defects characterized by reduced evoked movements which are exacerbated by exposure to atorvastatin, a compound known to cause RM. Importantly, RM features of tango2 KD are also associated with autophagy defects in zebrafish. Calpeptin treatment, a known activator of autophagy, is sufficient to rescue the locomotor function and improves autophagy in zebrafish. LC3-II levels of primary muscle cells of TANGO2 patients are also ameliorated by calpeptin treatment. Overall, we demonstrate that TANGO2 plays an important role in autophagy, and that autophagy efficiency is critical to prevent RM, thus giving rise to new therapeutic perspectives in the prevention of these life-threatening episodes in the context of TANGO2 pathology.

Published
2023

22. Integrative proteomics highlight presynaptic alterations and c-Jun misactivation as convergent pathomechanisms in ALS

Author

Amr Aly, Zsofia I. Laszlo, Sandeep Rajkumar, Tugba Demir, Nicole Hindley, Douglas J. Lamont, Johannes Lehmann, Mira Seidel, Daniel Sommer, Mirita Franz-Wachtel, Francesca Barletta, Simon Heumos, Stefan Czemmel, Edor Kabashi, Albert Ludolph, Tobias M. Boeckers, Christopher M. Henstridge, and Alberto Catanese

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease mainly affecting upper and lower motoneurons. Several functionally heterogeneous genes have been associated with the familial form of this disorder (fALS), depicting an extremely complex pathogenic landscape. This heterogeneity has limited the identification of an effective therapy, and this bleak prognosis will only improve with a greater understanding of convergent disease mechanisms. Recent evidence from human post-mortem material and diverse model systems has highlighted the synapse as a crucial structure actively involved in disease progression, suggesting that synaptic aberrations might represent a shared pathological feature across the ALS spectrum. To test this hypothesis, we performed the first comprehensive analysis of the synaptic proteome from post-mortem spinal cord and human iPSC-derived motoneurons carrying mutations in the major ALS genes. This integrated approach highlighted perturbations in the molecular machinery controlling vesicle release as a shared pathomechanism in ALS. Mechanistically, phosphoproteomic analysis linked the presynaptic vesicular phenotype to an accumulation of cytotoxic protein aggregates and to the pro-apoptotic activation of the transcription factor c-Jun, providing detailed insights into the shared pathobiochemistry in ALS. Notably, sub-chronic treatment of our iPSC-derived motoneurons with the fatty acid docosahexaenoic acid exerted a neuroprotective effect by efficiently rescuing the alterations revealed by our multidisciplinary approach. Together, this study provides strong evidence for the central and convergent role played by the synaptic microenvironment within the ALS spinal cord and highlights a potential therapeutic target that counteracts degeneration in a heterogeneous cohort of human motoneuron cultures.

Published
2023

23. Autophagy and ALS: mechanistic insights and therapeutic implications

Author

Edor Kabashi, Jason P. Chua, Sami J. Barmada, and Hortense de Calbiac

Subjects
0301 basic medicine, 030102 biochemistry & molecular biology, Amyotrophic Lateral Sclerosis, Neurodegeneration, Autophagy, PINK1, Cell Biology, Charged multivesicular body protein 2B, Biology, medicine.disease, Cell biology, 03 medical and health sciences, 030104 developmental biology, TANK-binding kinase 1, Frontotemporal Dementia, Mitophagy, Proteostasis, Unfolded Protein Response, medicine, biology.protein, Humans, TFEB, Molecular Biology, Mechanistic target of rapamycin
Abstract

Mechanisms of protein homeostasis are crucial for overseeing the clearance of misfolded and toxic proteins over the lifetime of an organism, thereby ensuring the health of neurons and other cells of the central nervous system. The highly conserved pathway of autophagy is particularly necessary for preventing and counteracting pathogenic insults that may lead to neurodegeneration. In line with this, mutations in genes that encode essential autophagy factors result in impaired autophagy and lead to neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS). However, the mechanistic details underlying the neuroprotective role of autophagy, neuronal resistance to autophagy induction, and the neuron-specific effects of autophagy-impairing mutations remain incompletely defined. Further, the manner and extent to which non-cell autonomous effects of autophagy dysfunction contribute to ALS pathogenesis are not fully understood. Here, we review the current understanding of the interplay between autophagy and ALS pathogenesis by providing an overview of critical steps in the autophagy pathway, with special focus on pivotal factors impaired by ALS-causing mutations, their physiologic effects on autophagy in disease models, and the cell type-specific mechanisms regulating autophagy in non-neuronal cells which, when impaired, can contribute to neurodegeneration. This review thereby provides a framework not only to guide further investigations of neuronal autophagy but also to refine therapeutic strategies for ALS and related neurodegenerative diseases.Abbreviations: ALS: amyotrophic lateral sclerosis; Atg: autophagy-related; CHMP2B: charged multivesicular body protein 2B; DPR: dipeptide repeat; FTD: frontotemporal dementia; iPSC: induced pluripotent stem cell; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; PINK1: PTEN induced kinase 1; RNP: ribonuclear protein; sALS: sporadic ALS; SPHK1: sphingosine kinase 1; TARDBP/TDP-43: TAR DNA binding protein; TBK1: TANK-binding kinase 1; TFEB: transcription factor EB; ULK: unc-51 like autophagy activating kinase; UPR: unfolded protein response; UPS: ubiquitin-proteasome system; VCP: valosin containing protein.

Published
2021

24. Deep phenotyping unstructured data mining in an extensive pediatric database to unravel a common KCNA2 variant in neurodevelopmental syndromes

Author

Giulia Barcia, Cyril Mignot, Edor Kabashi, Marie Hully, Rima Nabbout, Tommaso Lo Barco, Claude Cances, Isabelle Desguerre, Anna Kaminska, Nicolas Garcelon, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Toulouse [Toulouse], Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Health data- and model- driven Knowledge Acquisition (HeKA), Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École Pratique des Hautes Études (EPHE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), This work was supported by funding from The French National Research Agency (ANR) under 'Inverstissements d’Avenir' programs (reference ANR-10-IAHU-01)., and Gestionnaire, Hal Sorbonne Université

Subjects
0301 basic medicine, Computer science, [SDV]Life Sciences [q-bio], MEDLINE, 030105 genetics & heredity, computer.software_genre, Brief Communication, 03 medical and health sciences, Data Warehousing, Kv1.2 Potassium Channel, Data Mining, Electronic Health Records, Humans, Medical diagnosis, Child, Computational Biology, Infant, Newborn, Syndrome, Exome, Genetics (clinical), business.industry, Infant, Unstructured data, Newborn, Similitude, Data warehouse, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Vector space model, Identification (biology), Artificial intelligence, business, computer, Natural language processing
Abstract

International audience; Purpose: Electronic health records are gaining popularity to detect and propose interdisciplinary treatments for patients with similar medical histories, diagnoses, and outcomes. These files are compiled by different nonexperts and expert clinicians. Data mining in these unstructured data is a transposable and sustainable methodology to search for patients presenting a high similitude of clinical features.Methods: Exome and targeted next-generation sequencing bioinformatics analyses were performed at the Imagine Institute. Similarity Index (SI), an algorithm based on a vector space model (VSM) that exploits concepts extracted from clinical narrative reports was used to identify patients with highly similar clinical features.Results: Here we describe a case of "automated diagnosis" indicated by Dr. Warehouse, a biomedical data warehouse oriented toward clinical narrative reports, developed at Necker Children's Hospital using around 500,000 patients' records. Through the use of this warehouse, we were able to match and identify two patients sharing very specific clinical neonatal and childhood features harboring the same de novo variant in KCNA2.Conclusion: This innovative application of database clustering clinical features could advance identification of patients with rare and common genetic conditions and detect with high accuracy the natural history of patients harboring similar genetic pathogenic variants.

Published
2021

25. Behavioral And Physiological Analysis In A Zebrafish Model Of Epilepsy

Author

Adriana Dabacan, Edor Kabashi, Raul C. Mureşan, Sorana Ciura, and Hortense de Calbiac

Subjects
Epilepsy, General Immunology and Microbiology, biology, General Chemical Engineering, General Neuroscience, Regulator, biology.organism_classification, medicine.disease, DEPDC5, Epileptogenesis, General Biochemistry, Genetics and Molecular Biology, Disease Models, Animal, Seizures, medicine, Animals, Humans, Pentylenetetrazole, Premovement neuronal activity, Neuroscience, Zebrafish, PI3K/AKT/mTOR pathway, Organism
Abstract

Epilepsy represents one of the most common neurological disorders, affecting an estimated 50 million people worldwide. Recent advances in genetic research have uncovered a large spectrum of genes implicated in various forms of epilepsy, highlighting the heterogeneous nature of this disorder. Appropriate animal models are essential for investigating the pathological mechanisms triggered by genetic mutations implicated in epilepsy and for developing specialized, targeted therapies. In recent years, zebrafish has emerged as a valuable vertebrate organism for modeling epilepsies, with the use of both genetic manipulation and exposure to known epileptogenic drugs, such as pentylenetetrazole (PTZ), to identify novel anti-epileptic therapeutics. Deleterious mutations in the mTOR regulator DEPDC5 have been associated with various forms of focal epilepsies and knock-down of the zebrafish orthologue causes hyperactivity associated with spontaneous seizure-like episodes, as well as enhanced electrographic activity and characteristic turn wheel swimming. Here, we described the method involved in generating the DEPDC5 loss-of-function model and illustrate the protocol for assessing motor activity at 28 and 48 h post fertilization (hpf), as well as a method for recording field activity in the zebrafish optic tectum. An illustration of the effect of the epileptogenic drug PTZ on neuronal activity over time is also provided.

Published
2021

26. Loss of nucleoporin Nup50 is a risk factor for amyotrophic lateral sclerosis

Author

Jan H. Veldink, Edor Kabashi, Sylvie Dirrig-Grosch, Peter M Andersen, Najwa Ouali Alami, Luc Dupuis, Kirsten Sieverding, Axel Freischmidt, Natalia Mora, Albert C. Ludolph, Tobias M. Boeckers, Markus Margelisch, Philippe Couratier, Francesco Roselli, François Muratet, Andreas Sommacal, Chantal Sellier, Géraldine Lautrette, Erik Storkebaum, Markus Weber, Nick H.M. van Bakel, Stéphane Dieterlé, Stéphanie Millecamps, Kristel R. van Eijk, Jochen H. Weishaupt, Alberto Catanese, Kathrin Muller, Salim Megat, Xhuljana Mingaj, Christoph Neuwirth, Jason Sanogo, Hortense de Calbiac, and Deniz Yilmazer-Hanke

Subjects
Genetics, BCS1L, RNA splicing, Gene expression, medicine, RNA-binding protein, Genome-wide association study, Nucleoporin, Amyotrophic lateral sclerosis, Biology, medicine.disease, Gene
Abstract

The genetic basis of amyotrophic lateral sclerosis (ALS) is still incompletely understood. Using two independent genetic strategies, we show here that a large part of ALS heritability lies in genes expressed in inhibitory and excitatory neurons, especially at splicing sites regulated by a defined set of RNA binding proteins including TDP-43 and FUS. We conducted a transcriptome wide association study (TWAS) and identified 59 loci associated with ALS, including 14 previously identified genes, some of them not previously reaching significance in genome wide association studies. Among the 45 novel genes, several genes are involved in pathways known to be affected in ALS such as mitochondrial metabolism (including ATP5H, ATP5D, BCS1L), proteostasis (including COPS7A, G2E3, TMEM175, USP35) or gene expression and RNA metabolism (including ARID1B, ATXN3, PTBP2, TAF10). Interestingly, decreased expression of NUP50, a constrained gene encoding a nuclear pore basket protein, was associated with ALS in TWAS (Zscore = −4, FDR = 0.034). 11 potentially pathogenic variants (CADD score > 20) in 23 patients were identified in the NUP50 gene, most of them in the region of the protein mediating interaction with Importin alpha, and including 2 frameshift mutations. In cells from two patients carrying NUP50 variants, we showed decreased levels of NUP50 protein. Importantly, knocking down Nup50 led to increased neuronal death associated with p62 and nucleoporin inclusions in cultured neurons, and motor defects in Drosophila and zebrafish models. In all, our study identifies alterations in splicing in neurons as a critical pathogenic process in ALS, uncovers several new loci potentially contributing to ALS missing heritability, and provides genetic evidence linking nuclear pore defects to ALS.

Published
2021

27. Poly(A)-binding protein is an ataxin-2 chaperone that emulsifies biomolecular condensates

Author

Keren Lasker, Edor Kabashi, Victoria Shabardina, Guozhong Huang, Roberto Docampo, Anushka Sanyal, Georg Auburger, Yanniv Dorone, Iñaki Ruiz-Trillo, Anca Marian, Steven Boeynaems, Aaron D. Gitler, Garam Kim, and Nesli-Ece Sen

Subjects
Scaffold protein, History, Polymers and Plastics, biology, Chemistry, Sequence (biology), Protein aggregation, biology.organism_classification, Industrial and Manufacturing Engineering, Cell biology, Stress granule, Ataxin, Chaperone (protein), Poly(A)-binding protein, biology.protein, Short linear motif, Eukaryote, Business and International Management, Biogenesis
Abstract

SUMMARYBiomolecular condensation underlies the biogenesis of an expanding array of membraneless assemblies, including stress granules (SGs) which form under a variety of cellular stresses. Advances have been made in understanding the molecular grammar that dictates the behavior of a few key scaffold proteins that make up these phases but how the partitioning of hundreds of other SG proteins is regulated remains largely unresolved. While investigating the rules that govern the condensation of ataxin-2, a SG protein implicated in neurodegenerative disease, we unexpectedly identified a short 14aa sequence that acts as an ataxin-2 condensation switch and is conserved across the eukaryote lineage. We identify poly(A)-binding proteins as unconventional RNA-dependent chaperones that control this regulatory switch. Our results uncover a hierarchy of cis and trans interactions that fine-tune ataxin-2 condensation and reveal a new molecular function for ancient poly(A)-binding proteins as emulsifiers of biomolecular condensate proteins. These findings may inspire novel approaches to therapeutically target aberrant phases in disease.

Published
2021

28. Synaptic disruption and CREB‐regulated transcription are restored by K + channel blockers in ALS

Author

Alexander Wirth, Medhanie A. Mulaw, Dennis Freisem, Albert C. Ludolph, Alberto Catanese, Federica Torelli, Edor Kabashi, Francesco Roselli, Andrea Olivieri, Tobias M. Böckers, Daniel Sommer, Joanna Lipecka, Daniel Zytnicki, Valentin Ioannidis, David Massa-López, Sandeep Rajkumar, Ida Chiara Guerrera, Amr Aly, Saints-Pères Paris Institute for Neurosciences (SPINN - UMR 8003), and Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Induced Pluripotent Stem Cells, Optogenetics, CREB, Apamin, Neuroprotection, hiPSC, Synapse, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, synapse, medicine, Premovement neuronal activity, Animals, Humans, ddc:610, Amyotrophic lateral sclerosis, Transcription factor, motoneuron, Motor neurons, Motor Neurons, biology, drug therapy [Amyotrophic Lateral Sclerosis], Myatrophische Lateralsklerose, Neurodegenerative Diseases, medicine.disease, musculoskeletal system, genetics [Amyotrophic Lateral Sclerosis], 030104 developmental biology, Neuroprotective Agents, chemistry, nervous system, Therapy, Synapses, biology.protein, Molecular Medicine, ALS, Neuroscience, DDC 610 / Medicine & health, 030217 neurology & neurosurgery
Abstract

Synopsis image The lack of an effective treatment for ALS is calling for the development of novel therapeutic strategies. By using hiPSC���derived motoneurons and focusing on synapse���related processes, we provide new molecular targets rescuing the degenerative processes and neuronal loss in ALS. Human C9orf72���mutant motoneurons are characterized by reduced expression of synaptic gene, progressive loss of CREB activity and synapse loss. Similar alterations are observed also in motoneurons harboring TBK1 pathogenic mutations, and in primary neurons upon overexpression of poly(GA) aggregates. The K+ channel blockers Apamin and XE991 revert the CREB���dependent loss of synaptic contacts and rescue the degenerative phenotypes of ALS motoneurons., publishedVersion

Published
2021

29. Novel genome-editing-based approaches to treat motor neuron diseases: Promises and challenges

Author

Annarita, Miccio, Panagiotis, Antoniou, Sorana, Ciura, and Edor, Kabashi

Subjects
Gene Editing, Muscular Atrophy, Spinal, RNA Splicing, Amyotrophic Lateral Sclerosis, Oligonucleotides, Humans, Infant, Survival of Motor Neuron 1 Protein
Abstract

Motor neuron diseases are untreatable with common pharmacological approaches. Spinal muscular atrophy (SMA) is caused by SMN1 gene mutations leading to lowered SMN expression. Symptoms are alleviated in infants with a higher copy number of the SMN2 gene, which, however, displays a splicing defect resulting in low SMN levels. Amyotrophic lateral sclerosis (ALS) is caused by a number of mutations, with C9orf72 repeat expansions the most common genetic cause and SOD1 gain-of-function mutations the first genetic cause identified for this disease. Genetic therapies based on oligonucleotides that enhance SMN2 splicing and SMN production or lower SOD1 expression have shown promise in initial clinical trials for individuals with SMA and ALS harboring SOD1 mutations, respectively. Gene addition/silencing approaches using adeno-associated viruses (AAVs) are also currently under clinical investigation in trials for SMA and ALS. Here we provide a brief overview of these efforts and their advantages and challenges. We also review genome editing approaches aimed at correcting the disease-causing mutations or modulating the expression of genetic modifiers, e.g., by repairing SOD1 mutations or the SMN2 splicing defect or deleting C9orf72 expanded repeats. These studies have shown promising results to approach therapeutic trials that should significantly lower the progression of these deadly disorders.

Published
2021

30. Developmental and epilepsy spectrum of KCNB1 encephalopathy with long‐term outcome

Author

Rima Nabbout, Patrick Berquin, Sylvie Odent, Mathieu Kuchenbuch, Gwenaël Le Guyader, Marieke F. van Dooren, Jamel Chelly, Edor Kabashi, Melanie Jennesson, Giulia Barcia, Cyril Mignot, Tayeb Sekhara, Alexandra Afenjar, Marlène Rio, Anne Rolland, Claude Besmond, Andrés Rodríguez-Sacristán Cascajo, Gaetano Terrone, Isabelle Marey, Boris Keren, Alice Goldenberg, A.S. Lebre, Heather C Mefford, Gaetan Lesca, Anne de Saint Martin, Susanna Negrin, Nathalie Dorison, Hélène Maurey, Agnès Guët, David Geneviève, Marie Claire Y. de Wit, Jeremy L. Freeman, Pierre Meyer, Thierry Billette de Villemeur, Ingrid E. Scheffer, Katherine B. Howell, Anca Nica, Raphael Levy, Martino Montomoli, Renzo Guerrini, Elena Parrini, Candace T. Myers, Bertrand Isidor, Alice Poisson, Marion Gérard, Salima El Chehadeh, Lynette G. Sadleir, Julien Durigneux, Pascal Vrielynck, Amy L Schneider, Emmanuel Scalais, Laurence Hubert, Sophie Dupont, Vesna Brankovic, Damien Lederer, Hervé Isnard, Delphine Breuillard, Claire Bar, Alberto Danieli, Diane Doummar, Arnold Munnich, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Unité neurovasculaire et troubles cognitifs (Neuvacod), Université de Poitiers, Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Strasbourg, Centre for the Diagnosis and management of genetic psychiatric disorders [Bron] (GénoPsy), Centre Hospitalier le Vinatier [Bron], Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Rouen, Normandie Université (NU), CHU Amiens-Picardie, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Pitié-Salpêtrière [AP-HP], FP7 Ideas: European Research Council, National Health and Medical Research Council, Health Research Council of New Zealand, ANR‐10-IAHU‐01, Agence Nationale de la Recherche, Fondation Bettencourt Schueller, 602531, Seventh Framework Programme, ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), ANR‐10IAHU‐01, Agence Nationale de la Recherche, Clinical Genetics, Neurology, and Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1)

Subjects
0301 basic medicine, Adult, Male, Pediatrics, medicine.medical_specialty, Time Factors, Adolescent, autism spectrum disorders, [SDV]Life Sciences [q-bio], Encephalopathy, Severe epilepsy, Imaging data, Cohort Studies, 03 medical and health sciences, Epilepsy, Young Adult, 0302 clinical medicine, Shab Potassium Channels, drug-resistant epilepsy, Intellectual disability, medicine, Missense mutation, Humans, In patient, developmental and epileptic encephalopathy, Child, ComputingMilieux_MISCELLANEOUS, Retrospective Studies, Brain Diseases, sudden unexpected death in epilepsy, developmental encephalopathy, business.industry, Genetic Variation, Infant, Cognition, Electroencephalography, medicine.disease, potassium channels, 3. Good health, 030104 developmental biology, Treatment Outcome, Neurology, Child, Preschool, Female, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Objective: We aimed to delineate the phenotypic spectrum and long-term outcome of individuals with KCNB1 encephalopathy. Methods: We collected genetic, clinical, electroencephalographic, and imaging data of individuals with KCNB1 pathogenic variants recruited through an international collaboration, with the support of the family association “KCNB1 France.” Patients were classified as having developmental and epileptic encephalopathy (DEE) or developmental encephalopathy (DE). In addition, we reviewed published cases and provided the longterm outcome in patients older than 12 years from our series and from literature. Results: Our series included 36 patients (21 males, median age = 10 years, range = 1.6 months-34 years). Twenty patients (56%) had DEE with infantile onset seizures (seizure onset = 10 months, range = 10 days-3.5 years), whereas 16 (33%) had DE with late onset epilepsy in 10 (seizure onset = 5 years, range = 18 months-25 years) and without epilepsy in six. Cognitive impairment was more severe in individuals with DEE compared to those with DE. Analysis of 73 individuals with KCNB1 pathogenic variants (36 from our series and 37 published individuals in nine reports) showed developmental delay in all with severe to profound intellectual disability in 67% (n = 41/61) and autistic features in 56% (n = 32/57). Long-term outcome in 22 individuals older than 12 years (14 in our series and eight published individuals) showed poor cognitive, psychiatric, and behavioral outcome. Epilepsy course was variable. Missense variants were associated with more frequent and more severe epilepsy compared to truncating variants. Significance: Our study describes the phenotypic spectrum of KCNB1 encephalopathy, which varies from severe DEE to DE with or without epilepsy. Although cognitive impairment is worse in patients with DEE, long-term outcome is poor for most and missense variants are associated with more severe epilepsy outcome. Further understanding of disease mechanisms should facilitate the development of targeted therapies, much needed to improve the neurodevelopmental prognosis.

Published
2020

31. Freezing activity brief data from a new FUS mutant zebrafish line

Author

Edor Kabashi, Valérie Buée-Scherrer, Annis-Rayan Bourefis, Maria-Letizia Campanari, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Gestionnaire, Hal Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV]Life Sciences [q-bio], Mutant, LIGHT STIMULATION, Freezing response, lcsh:Computer applications to medicine. Medical informatics, Locomotor activity, 03 medical and health sciences, 0302 clinical medicine, Genetic model, Research article, Behaviour, Fragmentation (cell biology), Visual stimulation with the automatized viewpoint zebrabox system, lcsh:Science (General), Zebrafish, 030304 developmental biology, 0303 health sciences, Multidisciplinary, biology, Visual stimulation with the automatized, viewpoint zebrabox system, Zebrafish (Danio Rerio), biology.organism_classification, Cell biology, [SDV] Life Sciences [q-bio], FUS KO model, Zebrafish embryo, lcsh:R858-859.7, 030217 neurology & neurosurgery, Neuroscience, lcsh:Q1-390
Abstract

International audience; The data presented in this paper are related to the research article "Functional characterization of a FUS mutant zebrafish line as a novel genetic model for ALS". In this model the lack of fus causes reduced lifespan as well as impaired motor abilities associated with a decrease of motor neurons axons lenght and an increase of neuromuscular junctions fragmentation. Data in this article describes the global locomotor activity data at 3, 4 and 5 days post fertilization in WT, fus heterozygous (fus+/-) and fus homozygous (fus-/-) zebrafish embryos as a response to visual light stimulation, with particular attention on the freezing respose.

Published
2020

32. Functional Characterization of Neurofilament Light Splicing and Misbalance in Zebrafish

Author

Benoit J. Gentil, María Letizia Campanari, Edor Kabashi, Raphael Munoz-Ruiz, Doris Lou Demy, Heather D. Durham, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], Gestionnaire, Hal Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Gene isoform, Embryo, Nonmammalian, Neurofilament, amyotrophic lateral sclerosis (ALS), TDP-43, RNA Splicing, [SDV]Life Sciences [q-bio], Motor Activity, Primary transcript, TARDBP, Article, Cell Line, Polymerization, 03 medical and health sciences, 0302 clinical medicine, neurofilament light (NEFL), neurofilaments (NFs), Neurofilament Proteins, Animals, Humans, Cytoskeleton, Intermediate filament, Postural Balance, lcsh:QH301-705.5, Zebrafish, Motor Neurons, Sequence Homology, Amino Acid, biology, Chemistry, Gene Expression Regulation, Developmental, General Medicine, Zebrafish Proteins, biology.organism_classification, zebrafish, Axons, Cell biology, DNA-Binding Proteins, [SDV] Life Sciences [q-bio], Phenotype, 030104 developmental biology, lcsh:Biology (General), RNA splicing, Atrophy, amyotrophic lateral sclerosis (ALS), neurofilament light (NEFL), TDP-43, 030217 neurology & neurosurgery
Abstract

Neurofilaments (NFs), a major cytoskeletal component of motor neurons, play a key role in the differentiation, establishment and maintenance of their morphology and mechanical strength. The de novo assembly of these neuronal intermediate filaments requires the presence of the neurofilament light subunit (NEFL), whose expression is reduced in motor neurons in amyotrophic lateral sclerosis (ALS). This study used zebrafish as a model to characterize the NEFL homologue neflb, which encodes two different isoforms via a splicing of the primary transcript (neflbE4 and neflbE3). In vivo imaging showed that neflb is crucial for proper neuronal development, and that disrupting the balance between its two isoforms specifically affects the NF assembly and motor axon growth, with resultant motor deficits. This equilibrium is also disrupted upon the partial depletion of TDP-43 (TAR DNA-binding protein 43), an RNA-binding protein encoded by the gene TARDBP that is mislocalized into cytoplasmic inclusions in ALS. The study supports the interaction of the NEFL expression and splicing with TDP-43 in a common pathway, both biologically and pathogenetically.

Published
2020

33. Functional characterization of Neurofilament Light b splicing andmisbalance in zebrafish

Author

Heather D. Durham, Raphael Munoz-Ruiz, Doris Lou Demy, Edor Kabashi, María Letizia Campanari, and Benoit J. Gentil

Subjects
0303 health sciences, Neurofilament, biology, Chemistry, Protein subunit, RNA-binding protein, Primary transcript, biology.organism_classification, Cell biology, 03 medical and health sciences, 0302 clinical medicine, RNA splicing, Cytoskeleton, Intermediate filament, Zebrafish, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Neurofilaments (NFs), a major cytoskeletal component of motor neurons, play a key role in their differentiation, establishment and maintenance of their morphology and mechanical strength. Thede novoassembly of these neuronal intermediate filaments requires the presence of the neurofilament light subunit, NEFL, which expression is reduced in motor neurons in Amyotrophic Lateral Sclerosis (ALS). This study used zebrafish as a model to characterize the NEFL homologueneflb, which encodes two different isoforms via splicing of the primary transcript (neflbE4andneflbE3).In vivoimaging showed thatneflbis crucial for proper neuronal development, and that disrupting the balance between its two isoforms specifically affects NF assembly and motor axon growth, with resulting motor deficits. This equilibrium is also disrupted upon partial depletion of TDP-43, a RNA binding protein that is mislocalized into cytoplasmic inclusions in ALS. The study supports interaction of NEFL expression and splicing with TDP-43 in a common pathway, both biologically and pathogenetically.

Published
2020

34. Functional characterization of a FUS mutant zebrafish line as a novel genetic model for ALS

Author

Maria-Letizia Campanari, Annis-Rayan Bourefis, Valérie Buée-Scherrer, and Edor Kabashi

Subjects
0301 basic medicine, Motor neuron, Neuromuscular Junction, lcsh:RC321-571, 03 medical and health sciences, 0302 clinical medicine, Genetic model, medicine, Animals, Amyotrophic lateral sclerosis (ALS), Amyotrophic lateral sclerosis, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Zebrafish, Loss function, FUS, Acetylcholine receptor, Denervation, Motor Neurons, biology, Behavior, Animal, Models, Genetic, Neurodegeneration, Amyotrophic Lateral Sclerosis, biology.organism_classification, medicine.disease, HDAC4, Cell biology, Disease Models, Animal, 030104 developmental biology, Neurology, Mutation, RNA-Binding Protein FUS, Tau, 030217 neurology & neurosurgery
Abstract

Mutations in Fused in sarcoma (FUS), an RNA-binding protein, are known to cause Amyotrophic Lateral Sclerosis (ALS). However, molecular mechanisms due to loss of FUS function remain unclear and controversial. Here, we report the characterization and phenotypic analysis of a deletion mutant of the unique FUS orthologue in zebrafish where Fus protein levels are depleted. The homozygous mutants displayed a reduced lifespan as well as impaired motor abilities associated with specific cellular deficits, including decreased motor neurons length and neuromuscular junctions (NMJ) fragmentation. Furthermore, we demonstrate that these cellular impairments are linked to the misregulation of mRNA expression of acetylcholine receptor (AChR) subunits and histone deacetylase 4, markers of denervation and reinnervation processes observed in ALS patients. In addition, fus loss of function alters tau transcripts favoring the expression of small tau isoforms. Overall, this new animal model extends our knowledge on FUS and supports the relevance of FUS loss of function in ALS physiopathology.

Published
2020

35. Functional Characterisation of a GWAS Risk Locus Identifies GPX3 as a Lead Candidate Gene in ALS

Author

Michael J. Thompson, Noah Zaitlen, Edor Kabashi, Naomi R. Wray, Fei-Fei Cheng, Matthew C. Kiernan, Leanne Wallace, Shyuan T. Ngo, David Schultz, Robert D. Henderson, Susan Mathers, Merrilee Needham, Jean Giacomotto, Allan F. McRae, Christopher R. Bye, Leonard H. van den Berg, Bradley J. Turner, Anjali K. Henders, Restuadi Restuadi, Marta F. Nabais, Wouter van Rheenen, Frederik J. Steyn, Laura Ziser, Jan H. Veldink, Alexander Gusev, Ting Qi, Roel A. Ophoff, Pamela A. McCombe, and Fleur C. Garton

Subjects
Candidate gene, Expression quantitative trait loci, medicine, Genome-wide association study, Locus (genetics), Disease, Computational biology, Amyotrophic lateral sclerosis, Biology, medicine.disease, Gene, Genetic association
Abstract

Amyotrophic lateral sclerosis (ALS) is a complex late-onset, neurodegenerative disease with a genetic contribution to disease liability. Genome-wide association studies have identified eleven risk loci to date, including the TNIP1/GPX3 locus on chromosome five. Current association analysis data alone cannot determine the most plausible risk gene in this locus. Here, we undertake a comprehensive suite of studies to provide objective evidence to support or reject the relevance of these two genes. We use bioinformatic integration of genetic association data with omics reference data sets, in-vitro and in-vivo approaches to narrow down the likely candidate. TNIP1 and GPX3 are implicated in-silico (rs10463311 is an eQTL for these two genes). In-vivo expression analyses in ALS cases identify that GPX3 expression decreases with increased disability and rate of progression. Validation in-vivo, indicate GPX3 loss-of-function causes motor deficits in zebrafish embryos. Taken together, these results support GPX3 as being the ALS risk gene in this locus which has implications for understanding disease mechanisms and targeted therapeutic approaches.

Published
2020

36. Expanding the genetic and phenotypic relevance of KCNB1 variants in developmental and epileptic encephalopathies: 27 new patients and overview of the literature

Author

Delphine Breuillard, Isabelle Marey, Claire Bar, Tayeb Sekhara, Candace T. Myers, Diane Doummar, Alice Poisson, Hervé Isnard, Nathalie Dorison, Gwenaël Le Guyader, Arnold Munnich, Alexandra Afenjar, Anne de Saint Martin, Jamel Chelly, Gaetan Lesca, Gaetano Terrone, Rima Nabbout, Jeremy L. Freeman, David Geneviève, Sophie Dupont, Cyril Mignot, Katherine B. Howell, Giulia Barcia, Melanie Jennesson, Patrick Berquin, Sylvie Odent, Boris Keren, Ingrid E. Scheffer, Renzo Guerrini, Emmanuel Scalais, Thierry Billette de Villemeur, Martino Montomoli, Agnès Guët, Pierre Meyer, Anca Nica, Anne-Sophie Lebre, Edor Kabashi, Carla Marini, Amy L Schneider, Marion Gérard, Salima El Chehadeh, Heather C Mefford, Lynette G. Sadleir, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), American Memorial Hospital, Centre hospitalier universitaire de Poitiers (CHU Poitiers), University of Melbourne, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hospices Civils de Lyon (HCL), A Meyer Children's Hospital, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Equipe NEMESIS - Centre de Recherches de l'Institut du Cerveau et de la Moelle épinière (NEMESIS-CRICM), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Amiens-Picardie, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Hôpital de Hautepierre [Strasbourg], Hôpitaux Universitaires de Strasbourg, Hôpital Louis-Mourier, Colombes, France., Centre Hospitalier de Luxembourg [Luxembourg] (CHL), Rothschild Foundation Hospital, Paris., University of Washington [Seattle], Royal Children's Hospital, University of Melbourne, Melbourne, Victoria, Australia., A.Meyer Children's Hospital, CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Section of Pediatrics-Child Neurology Unit, Federico II University, 80131, Naples, Italy, Centre Hospitalier Interrégional Edith Cavell (CHIREC), Service de génétique [Reims], Centre Hospitalier Universitaire de Reims (CHU Reims), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CLAD-Ouest, CHU Rennes, France., University of Otago [Dunedin, Nouvelle-Zélande], Pediatric Neurology & Neurogenetics Unit and Laboratories, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI)-Children's Hospital A. Meyer, Epilepsy Research Centre, The Florey Institute of Neurosciences and Mental Health, Heidelberg, Victoria, Australia., Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Centre de référence des épilepsies rares [CHU Pitié-Salpêtrière], Unité fonctionnelle d'épilepsie [CHU Pitié-Salpêtrière], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Service de Neurologie [CHU Pitié-Salpêtrière], H2020 European Research Council, Health Research Council of New Zealand, Agence Nationale de la Recherche, Seventh Framework Programme, Fondation Bettencourt Schueller, European Research Council, Bar, C, Barcia, G, Jennesson, M, Le Guyader, G, Schneider, A, Mignot, C, Lesca, G, Breuillard, D, Montomoli, M, Keren, B, Doummar, D, de Villemeur, Tb, Afenjar, A, Marey, I, Gerard, M, Isnard, H, Poisson, A, Dupont, S, Berquin, P, Meyer, P, Genevieve, D, De Saint Martin, A, El Chehadeh, S, Chelly, J, Guët, A, Scalais, E, Dorison, N, Myers, Ct, Mefford, Hc, Howell, Kb, Marini, C, Freeman, Jl, Nica, A, Terrone, G, Sekhara, T, Lebre, A, Odent, S, Sadleir, Lg, Munnich, A, Guerrini, R, Scheffer, Ie, Kabashi, E, Nabbout, R, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [APHP], Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Hôpital Armand Trousseau, Hôpital Armand Trousseau, Paris, France., Centre de Référence déficiences intellectuelles de causes rares, GH Pitie-Salpêtrière-Charles Foix, F-, 75013, Paris, France., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Centre Hospitalier de Luxembourg, C.H.I.R.E.C, Brussels, Belgium., Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Children's Hospital A. Meyer-University of Florence (UNIFI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (ISC-MJ), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Naples Federico II = Università degli studi di Napoli Federico II, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Università degli Studi di Firenze = University of Florence (UniFI)-Children's Hospital A. Meyer, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Children's Hospital A. Meyer-Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-IFR70-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Service de Neurologie [CHU Pitié-Salpêtrière]

Subjects
Genotype, [SDV]Life Sciences [q-bio], Biology, Structure-Activity Relationship, 03 medical and health sciences, Epilepsy, Shab Potassium Channels, KCNB1, Intellectual disability, Genetic variation, Genetics, medicine, Humans, Missense mutation, Genetic Predisposition to Disease, Allele, developmental and epileptic encephalopathy, Alleles, Genetic Association Studies, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, 030305 genetics & heredity, Genetic Variation, medicine.disease, Axon initial segment, Phenotype, Neurodevelopmental Disorders, epilepsy, potassium channel
Abstract

International audience; Developmental and epileptic encephalopathies (DEE) refer to a heterogeneous group of devastating neurodevelopmental disorders. Variants in KCNB1 have been recently reported in patients with early-onset DEE. KCNB1 encodes the alpha subunit of the delayed-rectifier voltage-dependent potassium channel Kv 2.1. We review the 37 previously reported patients carrying 29 distinct KCNB1 variants and significantly expand the mutational spectrum describing 18 novel variants from 27 unreported patients. Most variants occur de novo and mainly consist of missense variants located on the voltage sensor and the pore domain of Kv 2.1. We also report the first inherited variant (p.Arg583*). KCNB1-related encephalopathies encompass a wide spectrum of neurodevelopmental disorders with predominant language difficulties and behavioral impairment. Eighty-five percent of patients developed epilepsies with variable syndromes and prognosis. Truncating variants in the C-terminal domain are associated with a less severe epileptic phenotype. Overall, this report provides an up-to-date review of the mutational and clinical spectrum of KCNB1, strengthening its place as a causal gene in DEEs and emphasizing the need for further functional studies to unravel the underlying mechanisms.

Published
2020

37. ALSUntangled No. 36: Accilion

Author

Gary L. Pattee, Muddasir Quereshi, Paul Wicks, Todd Levine, Chafic Karam, Edor Kabashi, Christen Shoesmith, Jonathan Goldstein, John T. Kissel, Jim Wymer, Fernando G. Vieira, Pamela Kittrell, Carmel Armon, Josep Gamez, Laurie Gutmann, Lisa Kinsley, Gleb Levitsky, Katherine Tindall, Janice Robertson, Yunxia Wang, Emma Fixsen, Carlayne E. Jackson, Stacy A. Rudnicki, Michael Benatar, Robert Bowser, Robin Conwit, Michael J. Strong, Bjorn Oskarsson, Rob Goldstein, Eric J. Sorenson, Alexander Sherman, Neta Zach, Kathy Mitchell, Peter M Andersen, Ahmad Ghavanini, Kristiana Salmon, Richard Bedlack, Nicholas J. Maragakis, Bonnie Gerecke, Jeffrey D. Rothstein, Leo McClusky, Paul E. Barkhaus, Efrat Carmi, Ginna Gonzalez, Jonathan Licht, Steve Perrin, Hiroshi Mitsumoto, Brett M. Morrison, Meraida Polak, Melanie Leitner, Tahseen Mozaffar, Lyle Ostrow, Orla Hardiman, Lorne Zinman, Daniel M. Pastula, Michael H. Rivner, Mazen M. Dimachkie, Steven Nash, Megan Grosso, Ashok Verma, James Heywood, Vivian E. Drory, Erik P. Pioro, Larry Phillips, Gregory T. Carter, Michael D. Weiss, Nazem Atassi, Jeffrey V. Rosenfeld, Khema Sharma, Yvonne Baker, Jon Baker, Christina Fournier, Kevin Boylan, Mark Bromberg, Tulio E. Bertorini, L. P. Rowland, Eric Valor, Sith Sathornsumetee, Rup Tandan, Colin Quinn, Jeremy M. Shefner, James A. Russell, Steve Kolb, Steven Novella, James Caress, Robert G. Miller, Mieko Ogino, George Sachs, Jonathan D. Glass, David Saperstein, Dan Moore, John Ravits, Terry Heiman-Patterson, Dallas Forshew, Catherine Lomen-Hoerth, Daniel MacGowan, Kate Dalton, Merit Cudkowicz, and Noah Lechtzin

Subjects
Risk, 0301 basic medicine, Clinical Trials as Topic, Pathology, medicine.medical_specialty, business.industry, Amyotrophic Lateral Sclerosis, medicine.disease, 03 medical and health sciences, Treatment Outcome, 030104 developmental biology, 0302 clinical medicine, Neurology, medicine, Animals, Humans, Neurology (clinical), Amyotrophic lateral sclerosis, business, 030217 neurology & neurosurgery
Published
2016

38. Depdc5 knockdown causes mTOR-dependent motor hyperactivity in zebrafish

Author

Hortense de Calbiac, Adriana Dabacan, Elise Marsan, Hervé Tostivint, Gabrielle Devienne, Saeko Ishida, Eric Leguern, Stéphanie Baulac, Raul C. Muresan, Edor Kabashi, Sorana Ciura, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Evolution des régulations endocriniennes (ERE), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Neurosciences Paris Seine (NPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), and Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2018

39. Defining the genetic connection linking amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD)

Author

Serena Lattante, Edor Kabashi, Guy A. Rouleau, and Sorana Ciura

Subjects
Neurodegeneration, Inheritance Patterns, Genetic Variation, Disease, Biology, Settore MED/03 - GENETICA MEDICA, medicine.disease, frontotemporal dementia, Translational Research, Biomedical, Disease Models, Animal, Risk Factors, Genetic marker, Genetic variation, Genetics, medicine, Animals, Humans, Genetic Predisposition to Disease, AMYOTROPHIC LATERAL SCLEROSIS, Allele, Amyotrophic lateral sclerosis, Neuroscience, Genetic Association Studies, Frontotemporal dementia
Abstract

Several genetic causes have been recently described for neurological diseases, increasing our knowledge of the common pathological mechanisms involved in these disorders. Mutation analysis has shown common causative factors for two major neurodegenerative disorders, ALS and FTD. Shared pathological and genetic markers as well as common neurological signs between these diseases have given rise to the notion of an ALS/FTD spectrum. This overlap among genetic factors causing ALS/FTD and the coincidence of mutated alleles (including causative, risk and modifier variants) have given rise to the notion of an oligogenic model of disease. In this review we summarize major advances in the elucidation of novel genetic factors in these diseases which have led to a better understanding of the common pathogenic factors leading to neurodegeneration.

Published
2015

40. ALSUntangled: Introducing The Table of Evidence

Author

Hubert Kwieciński, Dan Moore, Gary L. Pattee, Edor Kabashi, Chafic Karam, James Caress, Ashok Verma, Brett M. Morrison, Mieko Ogino, George Sachs, Orla Hardiman, Bonnie Gerecke, Vivian E. Drory, Hiroshi Mitsumoto, Gleb Levitsky, Josep Gamez, James Heywood, Nazem Atassi, Michael D. Weiss, Jeffrey V. Rosenfeld, Colin Quinn, Kathy Mitchell, Robin Conwit, Steven Novella, Mark B. Bromberg, Lewis P. Rowland, Jerry M. Belsh, Michael J. Strong, Todd Levine, Jonathan D. Glass, Yunxia Wang, Carlayne E. Jackson, Jon Baker, Muddasir Quereshi, Melanie Leitner, David Saperstein, Carmel Armon, Leo McClusky, Jonathan Licht, Terry Heiman-Patterson, Dallas Forshew, Laurie Gutmann, Pamela Kittrell, Jonathan Goldstein, Khema Sharma, Alexander Sherman, Efrat Carmi, Tahseen Mozaffar, James A. Russell, Merit Cudkowicz, Meraida Polak, Lorne Zinman, Michael Benatar, Jim Wymer, Christina Fournier, Noah Lechtzin, Eric Valor, Mazen M. Dimachkie, Steve Kolb, Megan Grosso, Katherine Tindall, Gregory T. Carter, Stacy A. Rudnicki, Lyle Ostrow, Eric J. Sorenson, Jeffrey D. Rothstein, Robert Bowser, Bjorn Oskarsson, Rup Tandan, Catherine Lomen-Hoerth, Daniel MacGowan, Peter M Andersen, Kate Dalton, Daniel M. Pastula, Craig Oster, Paul Wicks, Richard Bedlack, Michael H. Rivner, Nicholas J. Maragakis, John Ravits, Erik P. Pioro, Christen Shoesmith, John T. Kissel, Tulio E. Bertorini, Jeremy M. Shefner, Paul E. Barkhaus, Kevin Boylan, Jeff Dietz, Ginna Gonzalez, Sith Sathornsumetee, Larry Phillips, Steven Nash, Robert G. Miller, Janice Robertson, and Lisa Kinsley

Subjects
PubMed, medicine.medical_specialty, Evidence-Based Medicine, Physical medicine and rehabilitation, Neurology, business.industry, Amyotrophic Lateral Sclerosis, Humans, Medicine, Table (landform), Neurology (clinical), business
Published
2014

41. ALSUntangled No. 35: Hyperbaric Oxygen Therapy*

Author

Lisa Kinsley, Christen Shoesmith, Steven Nash, Peter M Andersen, John T. Kissel, Daniel M. Pastula, Josep Gamez, Nicholas J. Maragakis, Michael H. Rivner, Michael D. Weiss, Jeffrey V. Rosenfeld, James A. Russell, Kathy Mitchell, Steve Kolb, Melanie Leitner, Jim Wymer, Larry Phillips, Jon Baker, Jeffrey D. Rothstein, Erik P. Pioro, Katherine Tindall, Khema Sharma, Stacy A. Rudnicki, Jonathan D. Glass, James Caress, Janice Robertson, Meraida Polak, Tulio E. Bertorini, Paul Wicks, Yunxia Wang, Carlayne E. Jackson, L. P. Rowland, Megan Grosso, Bjorn Oskarsson, Carmel Armon, Leo McClusky, David Saperstein, Lorne Zinman, Laurie Gutmann, Gregory T. Carter, Robert Bowser, Gary L. Pattee, Kristiana Salmon, Brett M. Morrison, Richard Bedlack, Fernando G. Vieira, Orla Hardiman, Edor Kabashi, Sith Sathornsumetee, Vivian E. Drory, Jeremy M. Shefner, Emma Fixsen, Robert G. Miller, Steve Perrin, Michael Benatar, Hiroshi Mitsumoto, Alexander Sherman, Colin Quinn, Todd Levine, Neta Zach, Christina Fournier, Jonathan Goldstein, Lyle Ostrow, Mark Bromberg, Terry Heiman-Patterson, Dallas Forshew, Steven Novella, Mieko Ogino, George Sachs, John Ravits, Dan Moore, James Heywood, Merit Cudkowicz, Noah Lechtzin, Catherine Lomen-Hoerth, Daniel MacGowan, Kate Dalton, Ashok Verma, Yvonne Baker, Muddasir Quereshi, Kevin Boylan, Pamela Kittrell, Gleb Levitsky, Eric J. Sorenson, Robin Conwit, Rob Goldstein, Eric Valor, Rup Tandan, Nazem Atassi, Ahmad Ghavanini, Paul E. Barkhaus, Ginna Gonzalez, Efrat Carmi, Tahseen Mozaffar, Chafic Karam, Mazen M. Dimachkie, Michael J. Strong, Jonathan Licht, and Bonnie Gerecke

Subjects
Complementary Therapies, Male, 0301 basic medicine, Mice, Mice, Neurologic Mutants, 03 medical and health sciences, Clinical Trials, Phase II as Topic, 0302 clinical medicine, Hyperbaric oxygen, Animals, Humans, Medicine, Single-Blind Method, Amyotrophic lateral sclerosis, Hyperbaric Oxygenation, Clinical Trials, Phase I as Topic, business.industry, Amyotrophic Lateral Sclerosis, medicine.disease, Disease Models, Animal, Oxidative Stress, Treatment Outcome, 030104 developmental biology, Neurology, Anesthesia, Neurology (clinical), business, 030217 neurology & neurosurgery
Published
2016

42. Neuroleptics as therapeutic compounds stabilizing neuromuscular transmission in amyotrophic lateral sclerosis

Author

Lorne Zinman, Justin K. Ichida, Dina Aggad, Edor Kabashi, J. Alexander Parker, Xiao-Yan Wen, Alexandre La Fontaine, Gary A. B. Armstrong, Lawrence Korngut, Claudia Maios, Elsa Tremblay, Pierre Drapeau, Victor F. Rafuse, Shunmoogum A. Patten, Sorana Ciura, Richard Robitaille, Janet Petrillo, Jose A. Martinez, Jean-Pierre Julien, and Meijiang Liao

Subjects
0301 basic medicine, Drug Evaluation, Preclinical, Neuromuscular Junction, Neuromuscular transmission, Motility, Pharmacology, Neuromuscular junction, Calcium Channels, T-Type, Mice, 03 medical and health sciences, 0302 clinical medicine, Pimozide, Genetic model, Animals, Medicine, Amyotrophic lateral sclerosis, Caenorhabditis elegans, Zebrafish, biology, business.industry, Amyotrophic Lateral Sclerosis, Neurodegeneration, Drug Tolerance, General Medicine, Zebrafish Proteins, Neuromuscular Junction Diseases, medicine.disease, biology.organism_classification, 3. Good health, DNA-Binding Proteins, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Female, Calcium Channels, business, 030217 neurology & neurosurgery, Antipsychotic Agents, Research Article, medicine.drug
Abstract

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing, fatal disorder with no effective treatment. We used simple genetic models of ALS to screen phenotypically for potential therapeutic compounds. We screened libraries of compounds in C. elegans, validated hits in zebrafish, and tested the most potent molecule in mice and in a small clinical trial. We identified a class of neuroleptics that restored motility in C. elegans and in zebrafish, and the most potent was pimozide, which blocked T-type Ca2+ channels in these simple models and stabilized neuromuscular transmission in zebrafish and enhanced it in mice. Finally, a short randomized controlled trial of sporadic ALS subjects demonstrated stabilization of motility and evidence of target engagement at the neuromuscular junction. Simple genetic models are, thus, useful in identifying promising compounds for the treatment of ALS, such as neuroleptics, which may stabilize neuromuscular transmission and prolong survival in this disease.

Published
2017
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43. Fishing for causes and cures of motor neuron disorders

Author

Alexandra Lissouba, Edor Kabashi, Pierre Drapeau, Shunmoogum A. Patten, J. Alex Parker, and Gary A. B. Armstrong

Subjects
Hereditary spastic paraplegia, Neuroscience (miscellaneous), Danio, Drug Evaluation, Preclinical, Medicine (miscellaneous), lcsh:Medicine, Review, Biology, General Biochemistry, Genetics and Molecular Biology, Immunology and Microbiology (miscellaneous), medicine, lcsh:Pathology, HSP, Animals, Humans, SMA, Amyotrophic lateral sclerosis, Motor Neuron Disease, Zebrafish, Motor neuron disorders, Heterogeneous group, Drug discovery, lcsh:R, Spinal muscular atrophy, Anatomy, Motor neuron, medicine.disease, biology.organism_classification, Disease Models, Animal, medicine.anatomical_structure, ALS, Neuroscience, lcsh:RB1-214, Signal Transduction
Abstract

Motor neuron disorders (MNDs) are a clinically heterogeneous group of neurological diseases characterized by progressive degeneration of motor neurons, and share some common pathological pathways. Despite remarkable advances in our understanding of these diseases, no curative treatment for MNDs exists. To better understand the pathogenesis of MNDs and to help develop new treatments, the establishment of animal models that can be studied efficiently and thoroughly is paramount. The zebrafish (Danio rerio) is increasingly becoming a valuable model for studying human diseases and in screening for potential therapeutics. In this Review, we highlight recent progress in using zebrafish to study the pathology of the most common MNDs: spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP). These studies indicate the power of zebrafish as a model to study the consequences of disease-related genes, because zebrafish homologues of human genes have conserved functions with respect to the aetiology of MNDs. Zebrafish also complement other animal models for the study of pathological mechanisms of MNDs and are particularly advantageous for the screening of compounds with therapeutic potential. We present an overview of their potential usefulness in MND drug discovery, which is just beginning and holds much promise for future therapeutic development.

Published
2014

44. ALSUntangled No. 29: MitoQ

Author

Muddasir Quereshi, Bjorn Oskarsson, Peter M Andersen, Pamela Kittrell, Mark B. Bromberg, Gleb Levitsky, Richard Bedlack, Nicholas J. Maragakis, Leo McClusky, Michael J. Strong, Robin Conwit, Lewis P. Rowland, Efrat Carmi, Tahseen Mozaffar, Alexander Sherman, Mazen M. Dimachkie, Yunxia Wang, Megan Grosso, Brett M. Morrison, Carlayne E. Jackson, Eric J. Sorenson, Craig Oster, John Ravits, Meraida Polak, Orla Hardiman, Hubert Kwieciński, Terry Heiman-Patterson, Dallas Forshew, Christina Fournier, Jonathan Licht, Dan Moore, Carmel Armon, Gregory T. Carter, Gary L. Pattee, James Heywood, Katherine Tindall, Stacy A. Rudnicki, Edor Kabashi, Laurie Gutmann, Jonathan D. Glass, David Saperstein, Chafic Karam, Kevin Boylan, Daniel M. Pastula, Lorne Zinman, Lisa Kinsley, Eric Valor, Michael H. Rivner, Kathy Mitchell, Neta Zach, James A. Russell, Vivian E. Drory, Melanie Leitner, James Caress, Khema Sharma, Rup Tandan, Colin Quinn, Steven Novella, Ashok Verma, Larry Phillips, Catherine Lomen-Hoerth, Daniel MacGowan, Jim Wymer, Michael Benatar, Kate Dalton, Steve Kolb, Michael D. Weiss, Jeffrey V. Rosenfeld, Nazem Atassi, Robert Bowser, Jon Baker, Merit Cudkowicz, Noah Lechtzin, Jeffrey D. Rothstein, Paul Wicks, Steven Nash, Christen Shoesmith, John T. Kissel, Josep Gamez, Bonnie Gerecke, Hiroshi Mitsumoto, Janice Robertson, Paul E. Barkhaus, Ginna Gonzalez, Mieko Ogino, George Sachs, Todd Levine, Jonathan Goldstein, Jeremy M. Shefner, Tulio E. Bertorini, Robert G. Miller, Sith Sathornsumetee, Lyle Ostrow, Erik P. Pioro, and Jeff Dietz

Subjects
Pathology, medicine.medical_specialty, Ubiquinone, business.industry, Amyotrophic Lateral Sclerosis, Drug Evaluation, Preclinical, medicine.disease, Antioxidants, Disease Models, Animal, Oxidative Stress, Organophosphorus Compounds, Neurology, Animals, Humans, Medicine, Neurology (clinical), Amyotrophic lateral sclerosis, business
Published
2015

45. ALS Untangled No. 20: The Deanna Protocol

Author

Muddasir Quereshi, Pamela Kittrell, Jonathan D. Glass, Efrat Carmi, David Saperstein, Lisa Kinsley, Mark B. Bromberg, Christina Fournier, James Heywood, Eric Valor, Leo McClusky, Rup Tandan, Lyle Ostrow, Eric J. Sorenson, Jim Wymer, Noah Lechtzin, Megan Grosso, Carmel Armon, Todd Levine, Paul E. Barkhaus, Laurie Gutmann, Nazem Atassi, Ginna Gonzalez, Mazen M. Dimachkie, Daniel M. Pastula, Steven Nash, Tahseen Mozaffar, James A. Russell, Robert G. Miller, Hubert Kwieciński, Dan Moore, Michael H. Rivner, Ashok Verma, Craig Oster, John Ravits, Steve Kolb, Jonathan Goldstein, Robert Bowser, Steven Novella, Gregory T. Carter, Michael Benatar, Tulio E. Bertorini, Larry Phillips, Yunxia Wang, Carlayne E. Jackson, Kathy Mitchell, Orla Hardiman, Janice Robertson, Sith Sathornsumetee, Jeffrey D. Rothstein, Melanie Leitner, Lewis P. Rowland, Vivian E. Drory, James B. Caress, Jeremy M. Shefner, Mieko Ogino, George Sachs, Alexander Sherman, Michael J. Strong, Catherine Lomen-Hoerth, Paul Wicks, Erik P. Pioro, Daniel MacGowan, Terry Heiman-Patterson, Kevin B. Boylan, Bjorn Oskarsson, Dallas Forshew, Jonathan Licht, Josep Gamez, Katherine Tindall, Kate Dalton, Gleb Levitsky, Richard Bedlack, Hiroshi Mitsumoto, Gary L. Pattee, Jeff Dietz, Stacy A. Rudnicki, Bonnie Gerecke, Edor Kabashi, Robin Conwit, Peter M Andersen, Nicholas J. Maragakis, Meraida Polak, Michael D. Weiss, Jeffrey V. Rosenfeld, Jon Baker, Christen Shoesmith, John T. Kissel, and Khema Sharma

Subjects
medicine.medical_specialty, business.industry, Amyotrophic Lateral Sclerosis, medicine.disease, Physical medicine and rehabilitation, Neurology, Dietary Supplements, Coconut Oil, Animals, Humans, Plant Oils, Medicine, Nutrition Therapy, Neurology (clinical), Amyotrophic lateral sclerosis, business, Protocol (object-oriented programming)
Published
2013

46. Investigating the contribution of VAPB/ALS8 loss of function in amyotrophic lateral sclerosis

Author

François Gros-Louis, Luc Dupuis, Hajer El Oussini, Sylvie Dirrig-Grosch, Patrick A. Dion, Jean-Philippe Loeffler, Jérôme Sinniger, Nicolas Dupré, Pierre Drapeau, Jonathan R. McDearmid, William Camu, Guy A. Rouleau, Edor Kabashi, Inge A. Mejier, Valérie Bercier, Paul N. Valdmanis, David Hollinger, Vincent Meininger, and Frédérique René

Subjects
Male, Molecular Sequence Data, Mutation, Missense, Vesicular Transport Proteins, Mice, Transgenic, medicine.disease_cause, Cohort Studies, Mice, 03 medical and health sciences, 0302 clinical medicine, Mutant protein, Genetics, medicine, Animals, Humans, Amino Acid Sequence, Amyotrophic lateral sclerosis, Molecular Biology, Zebrafish, Genetics (clinical), Loss function, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Gene knockdown, Mutation, Base Sequence, biology, Amyotrophic Lateral Sclerosis, Membrane Proteins, General Medicine, Anatomy, Motor neuron, VAPB, biology.organism_classification, medicine.disease, Cell biology, medicine.anatomical_structure, Female, Sequence Alignment, 030217 neurology & neurosurgery
Abstract

The mutations P56S and T46I in the gene encoding vesicle-associated membrane protein-associated protein B/C (VAPB) cause ALS8, a familial form of amyotrophic lateral sclerosis (ALS). Overexpression of mutant forms of VAPB leads to cytosolic aggregates, suggesting a gain of function of the mutant protein. However, recent work suggested that the loss of VAPB function could be the major mechanism leading to ALS8. Here, we used multiple genetic and experimental approaches to study whether VAPB loss of function might be sufficient to trigger motor neuron degeneration. In order to identify additional ALS-associated VAPB mutations, we screened the entire VAPB gene in a cohort of ALS patients and detected two mutations (A145V and S160Δ). To directly address the contribution of VAPB loss of function in ALS, we generated zebrafish and mouse models with either a decreased or a complete loss of Vapb expression. Vapb knockdown in zebrafish led to swimming deficits. Mice knocked-out for Vapb showed mild motor deficits after 18 months of age yet had innervated neuromuscular junctions (NMJs). Importantly, overexpression of VAPB mutations were unable to rescue the motor deficit caused by Vapb knockdown in zebrafish and failed to cause a toxic gain-of-function defect on their own. Thus, Vapb loss of function weakens the motor system of vertebrate animal models but is on its own unable to lead to a complete ALS phenotype. Our findings are consistent with the notion that VAPB mutations constitute a risk factor for motor neuron disease through a loss of VAPB function.

Published
2013
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47. ALSUntangled 38: L-serine

Author

John Ravits, Jonathan D. Glass, David Saperstein, Ahmad Ghavanini, Erik P. Pioro, Efrat Carmi, Tahseen Mozaffar, Bjorn Oskarsson, Steven Nash, Kristiana Salmon, Richard Bedlack, Christina Fournier, Muddasir Quereshi, Pamela Kittrell, Eric J. Sorenson, Michael Benatar, Todd Levine, Jim Wymer, Carmel Armon, Laurie Gutmann, Jonathan Goldstein, Peter M Andersen, Michael D. Weiss, Lisa Kinsley, Paul Wicks, Jeffrey V. Rosenfeld, Ceri Weber, Ashok Verma, Nazem Atassi, Robert G. Miller, Robert Bowser, Josep Gamez, Bonnie Gerecke, Nicholas J. Maragakis, Brett M. Morrison, Megan Grosso, Gary L. Pattee, Orla Hardiman, Janice Robertson, Jon Baker, Edor Kabashi, Gregory T. Carter, Vivian E. Drory, Neta Zach, Merit Cudkowicz, Noah Lechtzin, Colin Quinn, Catherine Lomen-Hoerth, Daniel MacGowan, Terry Heiman-Patterson, Dallas Forshew, Eric Valour, Kate Dalton, Jeremy M. Shefner, James Heywood, Gleb Levitsky, Alexander Sherman, Robin Conwit, Rob Goldstein, Michael J. Strong, Katherine Tindall, Jeffrey D. Rothstein, Stacy A. Rudnicki, James A. Russell, Steve Kolb, Jonathan Licht, Chafic Karam, Steve Perrin, Hiroshi Mitsumoto, Lyle Ostrow, Leo McClusky, Yunxia Wang, Carlayne E. Jackson, Daniel M. Pastula, Michael H. Rivner, Larry Phillips, Rup Tandan, Paul E. Barkhaus, Ginna Gonzalez, Tulio E. Bertorini, L. P. Rowland, Yvonne Baker, Sith Sathornsumetee, Kevin Boylan, Mark Bromberg, Dan Moore, Fernando G. Vieira, Kathy Mitchell, Melanie Leitner, Mazen M. Dimachkie, James Caress, Meraida Polak, Lorne Zinman, Veronica Peschansky, Christen Shoesmith, John T. Kissel, Khema Sharma, Steven Novella, Emma Fixen, Keeli Hope Denson, Mieko Ogino, and George Sachs

Subjects
0301 basic medicine, Risk, Clinical Trials as Topic, Amyotrophic Lateral Sclerosis, L serine, Biology, medicine.disease, Molecular biology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Treatment Outcome, Neurology, medicine, Serine, Humans, Neurology (clinical), Amyotrophic lateral sclerosis, 030217 neurology & neurosurgery
Published
2016

48. ALSUntangled No. 37: Inosine

Author

Tulio E. Bertorini, L. P. Rowland, Paul Wicks, Steven Novella, Mark Bromberg, Sith Sathornsumetee, Lyle Ostrow, John Ravits, Sabrina Paganoni, Ginna Gonzalez, Edor Kabashi, Jonathan D. Glass, Josep Gamez, Tahseen Mozaffar, Robin Conwit, Richard Bedlack, Mazen M. Dimachkie, Michael Benatar, Eric J. Sorenson, Emma Fixsen, Yunxia Wang, Steve Kolb, Carlayne E. Jackson, James Caress, James Heywood, Nazem Atassi, Megan Grosso, Chafic Karam, Gregory T. Carter, Kevin Boylan, Orla Hardiman, Steven Nash, Kathy Mitchell, Dan Moore, Carmel Armon, Terry Heiman-Patterson, Dallas Forshew, Laurie Gutmann, Erik P. Pioro, Lisa Kinsley, Colin Quinn, Alexander Sherman, Janice Robertson, Kate Dalton, Larry Phillips, Peter M Andersen, Nicholas J. Maragakis, Katherine Tindall, Jon Baker, and Christen Shoesmith

Subjects
0301 basic medicine, Risk, Clinical Trials as Topic, business.industry, Amyotrophic Lateral Sclerosis, Pharmacology, medicine.disease, Inosine, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Treatment Outcome, Neurology, Medicine, Humans, Neurology (clinical), Amyotrophic lateral sclerosis, business, 030217 neurology & neurosurgery, medicine.drug
Published
2016

49. The most prevalent genetic cause of ALS-FTD, C9orf72 synergizes the toxicity of ATXN2 intermediate polyglutamine repeats through the autophagy pathway

Author

Edor Kabashi, Maria-Letizia Campanari, Chantal Sellier, Nicolas Charlet-Berguerand, Sorana Ciura, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and CHARLET BERGUERAND, NICOLAS

Subjects
0301 basic medicine, Genetics, Programmed cell death, [SDV]Life Sciences [q-bio], Autophagy, Neurodegeneration, Cell Biology, Biology, medicine.disease, TARDBP, [SDV] Life Sciences [q-bio], C9orf72 Protein, 03 medical and health sciences, 030104 developmental biology, C9orf72, medicine, Rab, Trinucleotide repeat expansion, Molecular Biology, ComputingMilieux_MISCELLANEOUS
Abstract

The most common genetic cause for amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD) is repeat expansion of a hexanucleotide sequence (GGGGCC) within the C9orf72 genomic sequence. To elucidate the functional role of C9orf72 in disease pathogenesis, we identified certain molecular interactors of this factor. We determined that C9orf72 exists in a complex with SMCR8 and WDR41 and that this complex acts as a GDP/GTP exchange factor for RAB8 and RAB39, 2 RAB GTPases involved in macroautophagy/autophagy. Consequently, C9orf72 depletion in neuronal cultures leads to accumulation of unresolved aggregates of SQSTM1/p62 and phosphorylated TARDBP/TDP-43. However, C9orf72 reduction does not lead to major neuronal toxicity, suggesting that a second stress may be required to induce neuronal cell death. An intermediate size of polyglutamine repeats within ATXN2 is an important genetic modifier of ALS-FTD. We found that coexpression of intermediate polyglutamine repeats (30Q) of ATXN2 combined with C9orf72 depletion increases the aggregation of ATXN2 and neuronal toxicity. These results were confirmed in zebrafish embryos where partial C9orf72 knockdown along with intermediate (but not normal) repeat expansions in ATXN2 causes locomotion deficits and abnormal axonal projections from spinal motor neurons. These results demonstrate that C9orf72 plays an important role in the autophagy pathway while genetically interacting with another major genetic risk factor, ATXN2, to contribute to ALS-FTD pathogenesis.

Published
2016

50. Loss of C9 ORF 72 impairs autophagy and synergizes with polyQ Ataxin‐2 to induce motor neuron dysfunction and cell death

Author

Frank Ruffenach, Chantal Sellier, Camille Julie Corbier, Nicolas Charlet-Berguerand, Maria-Letizia Campanari, Angeline Gaucherot, Sorana Ciura, Mustapha Oulad-Abdelghani, Edor Kabashi, Adeline Page, Isabelle Kolb-Cheynel, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHARLET BERGUERAND, NICOLAS, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Programmed cell death, [SDV]Life Sciences [q-bio], Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, C9orf72, medicine, Autophagy, Humans, News & Views, Amyotrophic lateral sclerosis, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Ataxin-2, Motor Neurons, General Immunology and Microbiology, C9orf72 Protein, Cell Death, General Neuroscience, Neurodegeneration, Amyotrophic Lateral Sclerosis, Proteins, Motor neuron, medicine.disease, Cell biology, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Ataxin, Frontotemporal Dementia, Peptides, 030217 neurology & neurosurgery
Abstract

An intronic expansion of GGGGCC repeats within the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). Ataxin-2 with intermediate length of polyglutamine expansions (Ataxin-2 Q30x) is a genetic modifier of the disease. Here, we found that C9ORF72 forms a complex with the WDR41 and SMCR8 proteins to act as a GDP/GTP exchange factor for RAB8a and RAB39b and to thereby control autophagic flux. Depletion of C9orf72 in neurons partly impairs autophagy and leads to accumulation of aggregates of TDP-43 and P62 proteins, which are histopathological hallmarks of ALS-FTD SMCR8 is phosphorylated by TBK1 and depletion of TBK1 can be rescued by phosphomimetic mutants of SMCR8 or by constitutively active RAB39b, suggesting that TBK1, SMCR8, C9ORF72, and RAB39b belong to a common pathway regulating autophagy. While depletion of C9ORF72 only has a partial deleterious effect on neuron survival, it synergizes with Ataxin-2 Q30x toxicity to induce motor neuron dysfunction and neuronal cell death. These results indicate that partial loss of function of C9ORF72 is not deleterious by itself but synergizes with Ataxin-2 toxicity, suggesting a double-hit pathological mechanism in ALS-FTD.

Published
2016

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