ATAXIN-2 intermediate-length polyglutamine expansions elicit ALS-associated metabolic and immune phenotypes
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-43<sup>Tg</sup>-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.
Authors
- Suzy Varderidou‐Minasian (ORCID: https://orcid.org/0000-0001-7879-4291)
- Sandra Kling
- David F. Gordon
- Kevin Talbot (ORCID: https://orcid.org/0000-0001-5490-1697)
- Domino K. Schlegel (ORCID: https://orcid.org/0000-0001-6194-4695)
- Mark H. Broekhoven
- Rianne de Jongh (ORCID: https://orcid.org/0009-0004-5530-3954)
- Emma Sudrià-Lopez (ORCID: https://orcid.org/0000-0002-6909-4020)
- Tessa L Verhoeff (ORCID: https://orcid.org/0000-0002-9621-1675)
- Youri Adolfs (ORCID: https://orcid.org/0000-0002-0011-1486)
- Pavol Zelina (ORCID: https://orcid.org/0009-0008-6776-663X)
- Daniëlle Vonk
- Enric Mocholí (ORCID: https://orcid.org/0000-0002-6614-3173)
- Nicky C.H. van Kronenburg
- R. Jeroen Pasterkamp (ORCID: https://orcid.org/0000-0003-1631-6440)
- Lauri M. Bloemenkamp
- Tijana Ljubikj
- Jan H. Veldink (ORCID: https://orcid.org/0000-0001-5572-9657)
- Jørgen Kjems (ORCID: https://orcid.org/0000-0003-4128-9317)
- Michael A. van Es (ORCID: https://orcid.org/0000-0002-7709-5883)
- Henk Karst (ORCID: https://orcid.org/0000-0003-2283-5642)
- Fabrizio Giuliani
- Oliver Harschnitz (ORCID: https://orcid.org/0000-0001-6496-881X)
- Marta Cañizares Luna
- Giel Korsten
- Onur Başak (ORCID: https://orcid.org/0000-0002-6864-3403)
- Renata Vieira de Sá (ORCID: https://orcid.org/0000-0002-6257-6115)
- Morten T. Venø (ORCID: https://orcid.org/0000-0002-4754-5193)
- Vamshidhar R. Vangoor (ORCID: https://orcid.org/0000-0003-0751-9772)
- Mayte Mars
- Sabine Seeler (ORCID: https://orcid.org/0000-0001-9348-4750)
- Henk-Jan Westeneng
- Teresa Calafat
- Leonard H. van den Berg
- Dianne M.A. van den Heuvel
- Lianne A J Peeters
Institutions
- Utrecht University (NL)
- Aarhus University (DK)
- University Medical Center Utrecht (NL)
- University of Oxford (GB)
- Human Technopole (IT)
- Omiics (Denmark) (DK)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-29
- DOI
- https://doi.org/10.1038/s41467-024-51676-0
- Citations
- 26
- Primary Topic
- Amyotrophic Lateral Sclerosis Research
- Type
- article
- Field-Weighted Citation Impact
- 9.60
Funders
- EU Joint Programme – Neurodegenerative Disease Research
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Adessium Foundation