ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization. Issue 2 (19th May 2020)

• Record Type: Journal Article
• Authors: Tazelaar, Gijs H P; Boeynaems, Steven; De Decker, Mathias; van Vugt, Joke J F A; Kool, Lindy; Goedee, H Stephan; McLaughlin, Russell L; Sproviero, William; Iacoangeli, Alfredo; Moisse, Matthieu; Jacquemyn, Maarten; Daelemans, Dirk; Dekker, Annelot M; van der Spek, Rick A; Westeneng, Henk-Jan; Kenna, Kevin P; Assialioui, Abdelilah; Da Silva, Nica; Povedano, Mónica; Pardina, Jesus S Mora; Hardiman, Orla; Salachas, François; Millecamps, Stéphanie; Vourc'h, Patrick; Corcia, Philippe; Couratier, Philippe; Morrison, Karen E; Shaw, Pamela J; Shaw, Christopher E; Pasterkamp, R Jeroen; Landers, John E; Van Den Bosch, Ludo; Robberecht, Wim; Al-Chalabi, Ammar; van den Berg, Leonard H; Van Damme, Philip; Veldink, Jan H; van Es, Michael A;
• Is Part Of: Brain communications. Volume 2:Issue 2(2020)
• Publication Date: 2020-05-19
• Subjects: amyotrophic lateral sclerosis -- trinucleotide repeat expansions -- DNA repeat expansion -- genetic association study; 616
• DOI: 10.1093/braincomms/fcaa064
• Languages: English
• ISSNs: 2632-1297

Abstract

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. Abstract : Repeat expansions are being identified as part of the complex genetic architecture of amyotrophic lateral sclerosis. This study shows a significant association between intermediate ATXN1 repeat expansions and amyotrophic lateral sclerosis, possibly via mislocalization of TDP-43, further emphasizing the role of polyglutamine expansions in the pathophysiology of amyotrophic lateral sclerosis. Graphical Abstract: