Influence of ATXN2 intermediate CAG repeats, 9bp duplication and alternative splicing on SCA3 pathogenesis
Year: 2025
Type: article
Study design: Observational Study
Abstract: Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease whose exact disease pathogenesis is not yet fully understood. We performed a genetic in-depth analysis of ataxin-2 (ATXN2), a gene that has already been described as a modulator of neurodegenerative diseases. We focused on the influence of an intermediate CAG repeat, a 9bp duplication (9bp), and isoform expression of ATXN2 on the pathogenesis of SCA3.Clinical and genetic data from a large European SCA3 cohort (total 390 probands) were analyzed. Fragment analyses were performed to determine the cytosine-adenine-guanine (CAG) repeat length and the 9bp duplication in ATXN2. RNA sequencing was performed on blood and cerebellum to evaluate ATXN2 isoform profile. Cell culture and SCA3 mice were used to investigate the influence of intermediate ATXN2 length on ataxin-3 protein abundance, aggregation, and cell viability.SCA3 carriers with an intermediate ATXN2 repeat presented a significant increase in non-ataxic symptoms. A greater age at onset and faster disease progression were found in SCA3 carriers with a 9bp duplication. Co-expression of ATXN2 and ATXN3 in cell models revealed an influence of ATXN2 on ataxin-3 abundance and aggregation patterns. Determination of soluble ATXN2 abundance demonstrated a significant genotype-independent reduction in mouse brain. Aggregate analyses indicated that ataxin-2 is not co-localized with ataxin-3-containing aggregates.Our comprehensive genetic study confirmed ATXN2 as a modulator of SCA3 pathogenesis, including onset and presence of clinical symptoms. For the first time, the ATXN2 isoform profile was compared in blood and cerebellar tissue, revealing a unique profile depending on the genotype and tissue. Here, a significant higher expression of ATXN2 splice variant type I in blood and significantly lower expression in cerebellar tissue were found compared to ATXN2 splice variant type II. Molecular and biochemical analyses in SCA3 mice and cell culture provide further evidence on mechanistic aspects, including differences in protein abundance and co-aggregation propensity. In summary, our study provides new insights into the modulatory effects of ATXN2 on SCA3 pathogenesis.
Authors: Marilena Lauerer, Jennifer Faber, Nicolas Casadei, Magda M. Santana, Georg Auburger, Michaela Pogoda, Jakob Admard, Lea Kaupp, Patricia Laura Kos, Mafalda Raposo, Manuela Lima, Luis Pereira de Almeida, Hector Garcia-Moreno, Paola Giunti, Jeroen de Vries, Bart P. van de Warrenburg, Judith van Gaalen, Marcus Grobe-Einsler, Berkan Koyak, Kathrin Reetz, Friedrich Erdlenbruch, Heike Jacobi, Jon Infante, Holger Hengel, Ludger Schöls, Thomas Klockgether, Olaf Rieß, Jeannette Hübener-Schmid, ESMI study group
Institutions: University of Tübingen, University of Bonn, University Hospital Bonn, German Center for Neurodegenerative Diseases, Centro de Neurociências e Biologia Celular, University of Coimbra, Goethe University Frankfurt, Universidade do Porto, i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Instituto de Biologia Molecular e Celular, Universidade dos Açores, Centro de Inovação em Biomedicina e Biotecnologia, University College London Hospitals NHS Foundation Trust, National Hospital for Neurology and Neurosurgery, UCL Queen Square Institute of Neurology, University College London, University Medical Center Groningen, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Rijnstate Hospital, Jülich Aachen Research Alliance, RWTH Aachen University, Essen University Hospital, University of Duisburg-Essen, University Hospital Heidelberg, Universidad de Cantabria, Biomedical Research Networking Center on Neurodegenerative Diseases, Marqués de Valdecilla University Hospital, Instituto de Investigación Marqués de Valdecilla, Hertie Institute for Clinical Brain Research
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,790
Funders: Fundo Regional para a Ciência e Tecnologia, EU Joint Programme – Neurodegenerative Disease Research, Deutsche Forschungsgemeinschaft, ZonMw, Eberhard Karls Universität Tübingen, Bundesministerium für Bildung und Forschung, Servier, Universitätsklinikum Tübingen, Medical Research Council, Fundação para a Ciência e a Tecnologia
Awards: G1517206771, HOME-, CLINIC- AND LAB-BASED QUANTITATIVE MEASURES TO CAPTURE AND TRACK THE PRECLINICAL STAGE OF MACHADO-JOSEPH DISEASE/SPINOCEREBELLAR ATAXIA TYPE 3, JPND Verbundprojekt ESMI: Europäische Spinozerebelläre Ataxie Typ 3 / Machado-Joseph-Krankheit Initiative, G7067039375, G8694460396
OpenAlex ID: W4412522887