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

Publication

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

Journal Paper/Review - May 19, 2020

Tazelaar Gijs H P, Boeynaems Steven, De Decker Mathias, Farei-Campagna Jan Marino, 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, PROJECT MINE ALS SEQUENCING CONSORTIUM, Povedano Monica, Mora Jesus S, Hardiman Orla, Salachas François, Millecamps Stéphanie, Vourc'h Patrick, Corcia Philippe, Couratier Philippe, Morrison Karen E, Openshaw Peter J M, 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

Citation

Tazelaar G, Boeynaems S, De Decker M, Farei-Campagna J, Kool L, Goedee H, McLaughlin R, Sproviero W, Iacoangeli A, Moisse M, Jacquemyn M, Daelemans D, Dekker A, Van Der Spek R, Westeneng H, Kenna K, Assialioui A, Da Silva N, PROJECT MINE ALS SEQUENCING CONSORTIUM, Povedano M, Mora J, Hardiman O, Salachas F, Millecamps S, Vourc'h P, Corcia P, Couratier P, Morrison K, Openshaw P, Shaw C, Pasterkamp R, Landers J, Van Den Bosch L, Robberecht W, Al-Chalabi A, van den Berg L, Van Damme P, Veldink J, van Es M. repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization. Brain Commun 2020; 2:fcaa064.

Type

Journal Paper/Review (English)

Journal

Brain Commun 2020; 2

Publication Date

May 19, 2020

Issn Electronic

2632-1297

Pages

fcaa064

Brief description/objective

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 , polyglutamine expansions in and polyalanine expansions in . 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 , suggested a similar disease association for the repeat expansion in . We, therefore, performed a large-scale international study in 11 700 individuals, in which we showed a significant association between intermediate repeat expansions and amyotrophic lateral sclerosis (=3.33 × 10). Subsequent functional experiments have shown that ATXN1 reduces the nucleocytoplasmic ratio of TDP-43 and enhances amyotrophic lateral sclerosis phenotypes in , further emphasizing the role of polyglutamine repeat expansions in the pathophysiology of amyotrophic lateral sclerosis.