Influence of ATXN2 intermediate CAG repeats, 9bp duplication and alternative splicing on SCA3 pathogenesis

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.

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Journal
Acta Neuropathologica Communications
Published
2025-07-19
DOI
https://doi.org/10.1186/s40478-025-02074-0
Citations
1
Primary Topic
Genetic Neurodegenerative Diseases
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article
Field-Weighted Citation Impact
0.91

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article

Influence of ATXN2 intermediate CAG repeats, 9bp duplication and alternative splicing on SCA3 pathogenesis

Judith van Gaalen, Héctor García‐Moreno, Jakob Admard, Bart P.C. van de Warrenburg et al.
1 citations
Acta Neuropathologica Communications
Genetic Neurodegenerative Diseases
0.91
article

Influence of ATXN2 intermediate CAG repeats, 9bp duplication and alternative splicing on SCA3 pathogenesis

Judith van Gaalen, Héctor García‐Moreno, Jakob Admard, Bart P.C. van de Warrenburg, Manuela Lima, Berkan Koyak, Jon Infante, Mafalda Raposo, Thomas Klockgether, Luís Pereira de Almeida, Magda M. Santana, Kathrin Reetz, Nicolas Casadei, Paola Giunti, Marcus Grobe‐Einsler, Jennifer Faber, Olaf Rieß, Georg Auburger, Heike Jacobi, Friedrich Erdlenbruch, Ludger J. Schöls, Michaela Pogoda, Jeannette Hübener‐Schmid, Holger Hengel, Jeroen J. de Vries, Marilena Lauerer, Lea Kaupp, Patricia Laura Kos
article en
1 citations

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.

Acta Neuropathologica CommunicationsVol. 13(1)
Goethe University Frankfurt (DE), Universidade dos Açores (PT), Universidad de Cantabria (ES), University Medical Center Groningen (NL), University College London Hospitals NHS Foundation Trust (GB), University of Bonn (DE), Radboud University Nijmegen (NL), Universidade do Porto (PT), Heidelberg University (DE), University Hospital Bonn (DE), German Center for Neurodegenerative Diseases (DE), University Hospital Heidelberg (DE), Radboud University Medical Center (NL), Biomedical Research Networking Center on Neurodegenerative Diseases (ES), Marqués de Valdecilla University Hospital (ES), Instituto de Investigación Marqués de Valdecilla (ES), Jülich Aachen Research Alliance (DE), Bernstein Center for Computational Neuroscience Tübingen (DE), Hertie Institute for Clinical Brain Research (DE), National Hospital for Neurology and Neurosurgery (GB), Rijnstate Hospital (NL), i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto (PT), University College London (GB), University of Duisburg-Essen (DE), University of Coimbra (PT), University of Tübingen (DE), RWTH Aachen University (DE)
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
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Openalex Percentile: Top 25%
Genetic Neurodegenerative Diseases
0.91
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