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We performed a genetic in-depth analysis of <jats:italic>ataxin-2<\/jats:italic> (<jats:italic>ATXN2)<\/jats:italic>, 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 <jats:italic>ATXN2<\/jats:italic> on the pathogenesis of SCA3.<\/jats:p>\n          <jats:p>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 <jats:italic>ATXN2<\/jats:italic>. RNA sequencing was performed on blood and cerebellum to evaluate <jats:italic>ATXN2<\/jats:italic> 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.<\/jats:p>\n          <jats:p>SCA3 carriers with an intermediate <jats:italic>ATXN2<\/jats:italic> 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.<\/jats:p>\n          <jats:p>Our comprehensive genetic study confirmed <jats:italic>ATXN2<\/jats:italic> 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 <jats:italic>ATXN2<\/jats:italic> on SCA3 pathogenesis.<\/jats:p>\n          <jats:p>\n            <jats:bold>Graphical Abstract<\/jats:bold>\n          <\/jats:p>","DOI":"10.1186\/s40478-025-02074-0","type":"journal-article","created":{"date-parts":[[2025,7,19]],"date-time":"2025-07-19T08:40:32Z","timestamp":1752914432000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Influence of ATXN2 intermediate CAG repeats, 9bp duplication and alternative splicing on SCA3 pathogenesis"],"prefix":"10.1186","volume":"13","author":[{"given":"Marilena","family":"Lauerer","sequence":"first","affiliation":[]},{"given":"Jennifer","family":"Faber","sequence":"additional","affiliation":[]},{"given":"Nicolas","family":"Casadei","sequence":"additional","affiliation":[]},{"given":"Magda M.","family":"Santana","sequence":"additional","affiliation":[]},{"given":"Georg","family":"Auburger","sequence":"additional","affiliation":[]},{"given":"Michaela","family":"Pogoda","sequence":"additional","affiliation":[]},{"given":"Jakob","family":"Admard","sequence":"additional","affiliation":[]},{"given":"Lea","family":"Kaupp","sequence":"additional","affiliation":[]},{"given":"Patricia Laura","family":"Kos","sequence":"additional","affiliation":[]},{"given":"Mafalda","family":"Raposo","sequence":"additional","affiliation":[]},{"given":"Manuela","family":"Lima","sequence":"additional","affiliation":[]},{"given":"Luis Pereira","family":"de Almeida","sequence":"additional","affiliation":[]},{"given":"Hector","family":"Garcia-Moreno","sequence":"additional","affiliation":[]},{"given":"Paola","family":"Giunti","sequence":"additional","affiliation":[]},{"given":"Jeroen","family":"de Vries","sequence":"additional","affiliation":[]},{"given":"Bart P.","family":"van de Warrenburg","sequence":"additional","affiliation":[]},{"given":"Judith","family":"van Gaalen","sequence":"additional","affiliation":[]},{"given":"Marcus","family":"Grobe-Einsler","sequence":"additional","affiliation":[]},{"given":"Berkan","family":"Koyak","sequence":"additional","affiliation":[]},{"given":"Kathrin","family":"Reetz","sequence":"additional","affiliation":[]},{"given":"Friedrich","family":"Erdlenbruch","sequence":"additional","affiliation":[]},{"given":"Heike","family":"Jacobi","sequence":"additional","affiliation":[]},{"given":"Jon","family":"Infante","sequence":"additional","affiliation":[]},{"given":"Holger","family":"Hengel","sequence":"additional","affiliation":[]},{"given":"Ludger","family":"Sch\u00f6ls","sequence":"additional","affiliation":[]},{"given":"Thomas","family":"Klockgether","sequence":"additional","affiliation":[]},{"given":"Olaf","family":"Rie\u00df","sequence":"additional","affiliation":[]},{"given":"Jeannette","family":"H\u00fcbener-Schmid","sequence":"additional","affiliation":[]},{"name":"ESMI study group","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2025,7,19]]},"reference":[{"key":"2074_CR1","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1038\/s41572-019-0074-3","volume":"5","author":"T Klockgether","year":"2019","unstructured":"Klockgether T, Mariotti C, Paulson HL (2019) Spinocerebellar ataxia. 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