ATAXIN-2 intermediate-length polyglutamine expansions elicit ALS-associated metabolic and immune phenotypes
Renata Vieira de Sá, Emma Sudrià-Lopez, Marta Cañizares Luna, Oliver Harschnitz, Dianne M.A. van den Heuvel, Sandra Kling, Daniëlle Vonk, Henk-Jan Westeneng, Henk Karst, Lauri M. Bloemenkamp, Suzy Varderidou‐Minasian, Domino K. Schlegel, Mayte Mars, Mark H. Broekhoven, Nicky C.H. van Kronenburg, Youri Adolfs, Vamshidhar R. Vangoor, Rianne de Jongh, Tijana Ljubikj, Lianne A J Peeters, Sabine Seeler, Enric Mocholí, Onur Başak, David F. Gordon, Fabrizio Giuliani, Tessa L Verhoeff, Giel Korsten, Teresa Calafat, Morten T. Venø, Jørgen Kjems, Kevin Talbot, Michael A. van Es, Jan H. Veldink, Leonard H. van den Berg, Pavol Zelina, R. Jeroen Pasterkamp
Abstract
Intermediate-length repeat expansions in ATAXIN-2 (ATXN2) are the strongest genetic risk factor for amyotrophic lateral sclerosis (ALS). At the molecular level, ATXN2 intermediate expansions enhance TDP-43 toxicity and pathology. However, whether this triggers ALS pathogenesis at the cellular and functional level remains unknown. Here, we combine patient-derived and mouse models to dissect the effects of ATXN2 intermediate expansions in an ALS background. iPSC-derived motor neurons from ATXN2-ALS patients show altered stress granules, neurite damage and abnormal electrophysiological properties compared to healthy control and other familial ALS mutations. In TDP-43Tg-ALS mice, ATXN2-Q33 causes reduced motor function, NMJ alterations, neuron degeneration and altered in vitro stress granule dynamics. Furthermore, gene expression changes related to mitochondrial function and inflammatory response are detected and confirmed at the cellular level in mice and human neuron and organoid models. Together, these results define pathogenic defects underlying ATXN2-ALS and provide a framework for future research into ATXN2-dependent pathogenesis and therapy. Intermediate-length repeat expansions in ATXN-2 are the strongest genetic risk factor for ALS. Here, the authors combine patient-derived motor neurons and organoids with mouse models to dissect the pathogenic effects of ATXN2 intermediate expansions.