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

Renata Vieira de Sá, Emma Sudria-Lopez, Marta Cañizares Luna, Oliver Harschnitz, Dianne M. A. Heuvel, Sandra Kling, Danielle Vonk, Henk-Jan Westeneng, Henk Karst, Lauri Bloemenkamp, Suzy Varderidou-Minasian, Domino K. Schlegel, Mayte Mars, Mark H. Broekhoven, Nicky C. H. Kronenburg, Youri Adolfs, Vamshidhar R. Vangoor, Rianne 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. Es, Jan H. Veldink, Leonard H. Berg, Pavol Zelina and R. Jeroen Pasterkamp ()
Additional contact information
Renata Vieira de Sá: University Medical Center Utrecht, Utrecht University
Emma Sudria-Lopez: University Medical Center Utrecht, Utrecht University
Marta Cañizares Luna: University Medical Center Utrecht, Utrecht University
Oliver Harschnitz: University Medical Center Utrecht, Utrecht University
Dianne M. A. Heuvel: University Medical Center Utrecht, Utrecht University
Sandra Kling: University Medical Center Utrecht, Utrecht University
Danielle Vonk: University Medical Center Utrecht, Utrecht University
Henk-Jan Westeneng: UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University
Henk Karst: University Medical Center Utrecht, Utrecht University
Lauri Bloemenkamp: University Medical Center Utrecht, Utrecht University
Suzy Varderidou-Minasian: University Medical Center Utrecht, Utrecht University
Domino K. Schlegel: University Medical Center Utrecht, Utrecht University
Mayte Mars: University Medical Center Utrecht, Utrecht University
Mark H. Broekhoven: University Medical Center Utrecht, Utrecht University
Nicky C. H. Kronenburg: University Medical Center Utrecht, Utrecht University
Youri Adolfs: University Medical Center Utrecht, Utrecht University
Vamshidhar R. Vangoor: University Medical Center Utrecht, Utrecht University
Rianne Jongh: University Medical Center Utrecht, Utrecht University
Tijana Ljubikj: University Medical Center Utrecht, Utrecht University
Lianne Peeters: University Medical Center Utrecht, Utrecht University
Sabine Seeler: Department of Molecular Biology and Genetics, Aarhus University
Enric Mocholi: University Medical Center Utrecht, Utrecht University
Onur Basak: University Medical Center Utrecht, Utrecht University
David Gordon: Oxford University
Fabrizio Giuliani: UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University
Tessa Verhoeff: University Medical Center Utrecht, Utrecht University
Giel Korsten: University Medical Center Utrecht, Utrecht University
Teresa Calafat Pla: University Medical Center Utrecht, Utrecht University
Morten T. Venø: Department of Molecular Biology and Genetics, Aarhus University
Jørgen Kjems: Department of Molecular Biology and Genetics, Aarhus University
Kevin Talbot: Oxford University
Michael A. Es: UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University
Jan H. Veldink: UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University
Leonard H. Berg: UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University
Pavol Zelina: University Medical Center Utrecht, Utrecht University
R. Jeroen Pasterkamp: University Medical Center Utrecht, Utrecht University

Nature Communications, 2024, vol. 15, issue 1, 1-25

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51676-0

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