title: The most prevalent genetic cause of ALS-FTD, C9orf72 synergizes the toxicity of ATXN2 intermediate polyglutamine repeats through the autophagy pathway.
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.
authors.affiliation: a Sorbonne Université, Université Pierre et Marie Curie (UPMC), Université de Paris 06, Unité Mixte 75, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 1127, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche 7225 Institut du Cerveau et de la Moelle Épinière (ICM) , Paris , France.
authors.forename: Sorana
authors.initials: S
authors.lastname: Ciura
authors.affiliation: b Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, Strasbourg University , Illkirch , France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Sellier
authors.affiliation: a Sorbonne Université, Université Pierre et Marie Curie (UPMC), Université de Paris 06, Unité Mixte 75, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 1127, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche 7225 Institut du Cerveau et de la Moelle Épinière (ICM) , Paris , France.
authors.forename: Maria-Letizia
authors.initials: ML
authors.lastname: Campanari
authors.affiliation: b Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, Strasbourg University , Illkirch , France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Charlet-Berguerand
authors.affiliation: a Sorbonne Université, Université Pierre et Marie Curie (UPMC), Université de Paris 06, Unité Mixte 75, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 1127, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche 7225 Institut du Cerveau et de la Moelle Épinière (ICM) , Paris , France.
authors.forename: Edor
authors.initials: E
authors.lastname: Kabashi
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D000818:Animals; D000067698:Ataxin-2 / Q000378:metabolism*; D001343:Autophagy; D000073885:C9orf72 Protein / Q000235:genetics* / Q000378:metabolism; D017173:Caenorhabditis elegans; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000473:pathology; D055785:Gene Knockdown Techniques; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice; D009046:Motor Neurons / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000071456:Sequestosome-1 Protein / Q000378:metabolism; D015027:Zebrafish / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000067698:Ataxin-2; D000073885:C9orf72 Protein; D004268:DNA-Binding Proteins; D010455:Peptides; C000602733:SQSTM1 protein, zebrafish; D000071456:Sequestosome-1 Protein; C585345:Tardbp protein, zebrafish; D029961:Zebrafish Proteins; C097188:polyglutamine; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; C000614241:TBK1L protein, zebrafish
keywords: ATXN2 (ataxin 2); C9orf72; TARDBP/TDP-43; TBK1; amytrophic lateral sclerosis (ALS); frontotemporal dementia (FTD); neurodegeneration; SQSTM1/p62; zebrafish