ATAXIN-2 intermediate-length polyglutamine expansions elicit ALS-associated metabolic and immune phenotypes

• DOI: 10.1038/s41467-024-51676-0
• Publication Date: 2024-08-29T11:03:48Z
• Authors: Renata Vieira de Sá; Emma Sudria-Lopez; Marta Cañizares Luna; Oliver Harschnitz; Dianne M. A. van ...; Sandra Kling; Danielle Vonk; Henk-Jan Westeneng; Henk Karst; Lauri Bloemenkamp; Suzy Varderidou-M...; Domino K. Schlegel; Mayte Mars; Mark H. Broekhoven; Nicky C. H. van K...; Youri Adolfs; Vamshidhar R. Van...; Rianne de Jongh; Tijana Ljubikj; Lianne Peeters; Sabine Seeler; Enric Mocholi; Onur Basak; David Gordon; Fabrizio Giuliani; Tessa Verhoeff; Giel Korsten; Teresa Calafat Pla; Morten T. Venø; Jørgen Kjems; Kevin Talbot; Michael A. van Es; Jan H. Veldink; Leonard H. van de...; Pavol Zelina; R. Jeroen Pasterkamp
• Keywords: Clinical phenotype

Intermediate-length repeat expansions in ATAXIN-2 (ATXN2) are the strongest genetic risk factor for amyotrophic lateral sclerosis (ALS). At molecular level, ATXN2 intermediate enhance TDP-43 toxicity and pathology. However, whether this triggers ALS pathogenesis at cellular functional level remains unknown. Here, we combine patient-derived mouse models to dissect effects of an background. iPSC-derived motor neurons from ATXN2-ALS patients show altered stress granules, neurite damage abnormal electrophysiological properties compared healthy control other familial mutations. In