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ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization.

ABSTRACT: Increasingly, repeat expansions are being identified as part of the complex genetic architecture of amyotrophic lateral sclerosis. To date, several repeat expansions have been genetically associated with the disease: intronic repeat expansions in C9orf72, polyglutamine expansions in ATXN2 and polyalanine expansions in NIPA1. Together with previously published data, the identification of an amyotrophic lateral sclerosis patient with a family history of spinocerebellar ataxia type 1, caused by polyglutamine expansions in ATXN1, suggested a similar disease association for the repeat expansion in ATXN1. We, therefore, performed a large-scale international study in 11 700 individuals, in which we showed a significant association between intermediate ATXN1 repeat expansions and amyotrophic lateral sclerosis (P = 3.33 × 10^-7). Subsequent functional experiments have shown that ATXN1 reduces the nucleocytoplasmic ratio of TDP-43 and enhances amyotrophic lateral sclerosis phenotypes in Drosophila, further emphasizing the role of polyglutamine repeat expansions in the pathophysiology of amyotrophic lateral sclerosis.

SUBMITTER: Tazelaar GHP

PROVIDER: S-EPMC7425293 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization.

Tazelaar Gijs H P GHP Boeynaems Steven S De Decker Mathias M van Vugt Joke J F A JJFA Kool Lindy L Goedee H Stephan HS McLaughlin Russell L RL Sproviero William W Iacoangeli Alfredo A Moisse Matthieu M Jacquemyn Maarten M Daelemans Dirk D Dekker Annelot M AM van der Spek Rick A RA Westeneng Henk-Jan HJ Kenna Kevin P KP Assialioui Abdelilah A Da Silva Nica N Povedano Mónica M Pardina Jesus S Mora JSM Hardiman Orla O Salachas François F Millecamps Stéphanie S Vourc'h Patrick P Corcia Philippe P Couratier Philippe P Morrison Karen E KE Shaw Pamela J PJ Shaw Christopher E CE Pasterkamp R Jeroen RJ Landers John E JE Van Den Bosch Ludo L Robberecht Wim W Al-Chalabi Ammar A van den Berg Leonard H LH Van Damme Philip P Veldink Jan H JH van Es Michael A MA

Brain communications 20200519 2

Increasingly, repeat expansions are being identified as part of the complex genetic architecture of amyotrophic lateral sclerosis. To date, several repeat expansions have been genetically associated with the disease: intronic repeat expansions in C9orf72, polyglutamine expansions in ATXN2 and polyalanine expansions in NIPA1. Together with previously published data, the identification of an amyotrophic lateral sclerosis patient with a family history of spinocerebellar ataxia ...[more]

PMID: 32954321

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Project description:Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive motoneuron loss. Redistribution of transactive response deoxyribonucleic acid-binding protein 43 from the nucleus to the cytoplasm and the presence of cystatin C-positive Bunina bodies are considered pathological hallmarks of amyotrophic lateral sclerosis, but their significance has not been fully elucidated. Since all reported rodent transgenic models using wild-type transactive response deoxyribonucleic acid-binding protein 43 failed to recapitulate these features, we expected a species difference and aimed to make a non-human primate model of amyotrophic lateral sclerosis. We overexpressed wild-type human transactive response deoxyribonucleic acid-binding protein 43 in spinal cords of cynomolgus monkeys and rats by injecting adeno-associated virus vector into the cervical cord, and examined the phenotype using behavioural, electrophysiological, neuropathological and biochemical analyses. These monkeys developed progressive motor weakness and muscle atrophy with fasciculation in distal hand muscles first. They also showed regional cytoplasmic transactive response deoxyribonucleic acid-binding protein 43 mislocalization with loss of nuclear transactive response deoxyribonucleic acid-binding protein 43 staining in the lateral nuclear group of spinal cord innervating distal hand muscles and cystatin C-positive cytoplasmic aggregates, reminiscent of the spinal cord pathology of patients with amyotrophic lateral sclerosis. Transactive response deoxyribonucleic acid-binding protein 43 mislocalization was an early or presymptomatic event and was later associated with neuron loss. These findings suggest that the transactive response deoxyribonucleic acid-binding protein 43 mislocalization leads to α-motoneuron degeneration. Furthermore, truncation of transactive response deoxyribonucleic acid-binding protein 43 was not a prerequisite for motoneuronal degeneration, and phosphorylation of transactive response deoxyribonucleic acid-binding protein 43 occurred after degeneration had begun. In contrast, similarly prepared rat models expressed transactive response deoxyribonucleic acid-binding protein 43 only in the nucleus of motoneurons. There is thus a species difference in transactive response deoxyribonucleic acid-binding protein 43 pathology, and our monkey model recapitulates amyotrophic lateral sclerosis pathology to a greater extent than rodent models, providing a valuable tool for studying the pathogenesis of sporadic amyotrophic lateral sclerosis.

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ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization.

Publications

<i>ATXN1</i> repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization.

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ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization.

Publications

&lt;i&gt;ATXN1&lt;/i&gt; repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization.

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OmicsDI is part of the ELIXIR infrastructure

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<i>ATXN1</i> repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization.