ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization
Tazelaar GHP., Boeynaems S., De Decker M., van Vugt JJFA., Kool L., Goedee HS., McLaughlin RL., Sproviero W., Iacoangeli A., Moisse M., Jacquemyn M., Daelemans D., Dekker AM., van der Spek RA., Westeneng H-J., Kenna KP., Assialioui A., Da Silva N., Akçimen F., Al Khleifat A., Al-Chalabi A., Andersen P., Basak AN., Bauer DC., Blair I., Brands WJ., Byrne RP., Calvo A., Gonzalez YC., Chio A., Cooper-Knock J., Corcia P., Couratier P., de Carvalho M., Dekker AM., Drory VE., Eitan C., Redondo AG., Gellera C., Glass JD., Gotkine M., Hardiman O., Hornstein E., Iacoangeli A., Kenna KP., Kenna B., Kiernan MC., Kocoglu C., Kooyman M., Landers JE., Alonso VL., McLaughlin RL., Middelkoop B., Mill J., Mitne-Neto M., Moisse M., Mora Pardina JS., Morrison KE., Pinto S., Gromicho M., Panadés MP., Pulit SL., Ratti A., Robberecht W., Schellevis RD., Shatunov A., Shaw CE., Shaw PJ., Silani V., Sproviero W., Staiger C., Tazelaar GHP., Ticozzi N., Tunca C., Twine NA., van Damme P., van den Berg LH., van der Spek RA., van Doormaal PTC., van Eijk KR., van Es MA., van Rheenen W., van Vugt JJFA., Veldink JH., Visscher PM., Vourc’h P., Weber M., Williams KL., Wray N., Yang J., Zatz M., Zhang K., Povedano M., Pardina JSM., Hardiman O., Salachas F., Millecamps S., Vourc’h P., Corcia P., Couratier P., Morrison KE., Shaw PJ., Shaw CE., Pasterkamp RJ., Landers JE., Van Den Bosch L., Robberecht W., Al-Chalabi A., van den Berg LH., Van Damme P., Veldink JH., van Es MA.
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.