Evidence map›Paper›PMID 40684213›Full record

ArticleActa neuropathologica communications2025

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

Marilena Lauerer, Jennifer Faber, Nicolas Casadei, Magda M Santana, Georg Auburger, Michaela Pogoda, Jakob Admard, Lea Kaupp, Patricia Laura Kos, Mafalda Raposo and 19 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Acta neuropathologica communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Article
  2. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

29 authors.

Marilena LauererInstitute for Medical Genetics and Applied Genomics, University of Tübingen, Nägelestraße 5, 72074, Tübingen, Germany.
Jennifer FaberGerman Center for Neurodegenerative Diseases, Bonn, Germany.
Nicolas CasadeiInstitute for Medical Genetics and Applied Genomics, University of Tübingen, Nägelestraße 5, 72074, Tübingen, Germany.
Magda M SantanaCenter for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal.
Georg AuburgerExperimental Neurology, Clinic of Neurology, Medical School, Goethe University, Frankfurt am Main, Germany.
Michaela PogodaInstitute for Medical Genetics and Applied Genomics, University of Tübingen, Nägelestraße 5, 72074, Tübingen, Germany.
Jakob AdmardInstitute for Medical Genetics and Applied Genomics, University of Tübingen, Nägelestraße 5, 72074, Tübingen, Germany.
Lea KauppInstitute for Medical Genetics and Applied Genomics, University of Tübingen, Nägelestraße 5, 72074, Tübingen, Germany.
Patricia Laura KosInstitute for Medical Genetics and Applied Genomics, University of Tübingen, Nägelestraße 5, 72074, Tübingen, Germany.
Mafalda RaposoIBMC - Instituto de Biologia Molecular e Celular, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, i3S, Portugal.
Manuela LimaUMIB - Unit for Multidisciplinary Research in Biomedicine, ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal.
Luis Pereira de AlmeidaCenter for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.
Hector Garcia-MorenoAtaxia Centre, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK.
Paola GiuntiAtaxia Centre, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK.
Jeroen de VriesUniversity Medical Center Groningen, Neurology, Groningen, The Netherlands.
Bart P van de WarrenburgDepartment of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Judith van GaalenDepartment of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Marcus Grobe-EinslerGerman Center for Neurodegenerative Diseases, Bonn, Germany.
Berkan KoyakGerman Center for Neurodegenerative Diseases, Bonn, Germany.
Kathrin ReetzDepartment of Neurology, RWTH Aachen University, Aachen, Germany.
Friedrich ErdlenbruchDepartment of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Heike JacobiDepartment of Neurology, University Hospital of Heidelberg, Heidelberg, Germany.
Jon InfanteUniversity Hospital Marqués de Valdecilla-IDIVAL, Santander, Spain.
Holger HengelDepartment of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research & Center of Neurology, University of Tübingen, Tübingen, Germany.
Ludger SchölsDepartment of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research & Center of Neurology, University of Tübingen, Tübingen, Germany.
Thomas KlockgetherGerman Center for Neurodegenerative Diseases, Bonn, Germany.
Olaf RießInstitute for Medical Genetics and Applied Genomics, University of Tübingen, Nägelestraße 5, 72074, Tübingen, Germany.
Jeannette Hübener-SchmidInstitute for Medical Genetics and Applied Genomics, University of Tübingen, Nägelestraße 5, 72074, Tübingen, Germany. Jeannette.huebener@med.uni-tuebingen.de.
ESMI study group

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

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.

Indexed as

Alternative SplicingAtaxin-2Machado-Joseph DiseaseAdultAgedAnimalsAtaxin-3Cohort StudiesFemaleGene DuplicationHumansMaleMiceMice, TransgenicMiddle AgedTrinucleotide Repeat ExpansionAtaxin-2Ataxin-3ATXN2 protein, humanATXN2Gene modifierGenotype-phenotype correlationMJDSCA3

Identifiers

PMID40684213
PMCPMC12275423

What Socratic holds

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LicenceCC BY
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.