{ "abstract": "Intranuclear localization of the affected protein ataxin-3 is critical for the pathogenesis of spinocerebellar ataxia type 3 (SCA3). The nuclear-cytoplasmic transporter karyopherin alpha 3 (KPNA3) has been demonstrated to play an essential role in the pathophysiology of this disorder. In this study, we characterized the single nucleotide polymorphism (SNP) rs11618521, located in the KPNA3 promoter, as a genetic modifier of the age at onset in SCA3 and a regulator of the KPNA3 promoter activity. Moreover, we identified the transcription factor Nanog homeobox (NANOG) as a key regulator exerting allele-specific modulatory effects on the KPNA3 promoter activity, thereby modulating expression and contributing to SCA3-associated pathogenic mechanisms. Pharmacological inhibition of NANOG reduced KPNA3 levels and ameliorated aggregate formation. In conclusion, we identified variant rs11618521 as a regulator of KPNA3 promoter activity and as a genetic modifier of SCA3. Moreover, we provide mechanistic insights that may guide future-targeted therapeutic strategies.", "abstract_shown": true, "affiliations": [ "Institute of Medical Genetics and Applied Genomics, University of Tübingen, Nägelestraße 5, 72076, Tübingen, Germany.", "Department of Human Genetics, Ruhr University Bochum, 44801, Bochum, Germany.", "Department of Clinical Epidemiology and Applied Biometry, University of Tübingen, 72076, Tübingen, Germany.", "Department of Neurology, Meir Medical Center, Tel Aviv University, 69978, Tel Aviv, Israel.", "Universidade Estadual de Campinas (UNICAMP), Campinas, 13083-970, Brazil.", "Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, 90035-903, Brazil.", "Departamento de Bioquímica, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, 90035-003, Brazil.", "Centros de Pesquisa Clínica E Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, 90035‑903, Brazil.", "Departamento de Medicina Interna, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, 90035-903, Brazil.", "Neurogenetics Working Group, Universidad Científica del Sur, 15067, Lima, Peru.", "Neurogenetics Research Center, Instituto Nacional de Ciencias Neurológicas, 15003, Lima, Peru.", "Centogene GmbH, 18055, Rostock, Germany.", "Pomeranian Medical University PUM, 70-204, Szczecin, Poland.", "Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, 72076, Tübingen, Germany.", "German Center of Neurodegenerative Diseases (DZNE), 72076, Tübingen, Germany.", "Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, 6525, Nijmegen, Netherlands.", "Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris, France.", "German Center for Neurodegenerative Diseases (DZNE), 53127, Bonn, Germany.", "Institute of Medical Genetics and Applied Genomics, University of Tübingen, Nägelestraße 5, 72076, Tübingen, Germany. thorsten.schmidt@med.uni-tuebingen.de." ], "article_type": "research article", "arxiv": null, "author_total": 29, "authors": [ { "affs": [ 0 ], "name": "Hezhou Han", "orcid": "0000-0002-3489-0289" }, { "affs": [ 0 ], "name": "Leah Czisch" }, { "affs": [ 0 ], "name": "Manuel Pascal Wanner" }, { "affs": [ 0, 1 ], "name": "Jonasz Jeremiasz Weber", "orcid": "0000-0003-3758-1569" }, { "affs": [ 0 ], "name": "Miriam Christina Dieterle" }, { "affs": [ 0 ], "name": "Carolina Alexandra Licia Schroeder" }, { "affs": [ 0, 1 ], "name": "Pengfei Qi" }, { "affs": [ 0 ], "name": "Junbo Zhou" }, { "affs": [ 0 ], "name": "Jaqueline Jung" }, { "affs": [ 0 ], "name": "Wenxu Zheng" }, { "affs": [ 0 ], "name": "Fubo Cheng", "orcid": "0000-0001-7215-8593" }, { "affs": [ 0 ], "name": "Priscila Pereira Sena", "orcid": "0000-0002-2061-5470" }, { "affs": [ 0, 1 ], "name": "Florian Fath", "orcid": "0000-0002-6564-4291" }, { "affs": [ 2 ], "name": "Gunnar Blumenstock" }, { "affs": [ 3 ], "name": "Carlos R Gordon", "orcid": "0000-0003-1576-214X" }, { "affs": [ 3 ], "name": "Roy Zaltzman" }, { "affs": [ 4 ], "name": "Marcondes C França", "orcid": "0000-0003-0898-2419" }, { "affs": [ 5, 6, 7 ], "name": "Maria-Luiza Saraiva-Pereira", "orcid": "0000-0003-3905-9563" }, { "affs": [ 5, 7, 8 ], "name": "Laura Bannach Jardim", "orcid": "0000-0001-6907-5068" }, { "affs": [ 9, 10 ], "name": "Mario R Cornejo-Olivas", "orcid": "0000-0001-6313-5680" }, { "affs": [ 0, 11, 12 ], "name": "Peter Bauer", "orcid": "0000-0001-9414-4555" }, { "affs": [ 13, 14 ], "name": "Ludger Schöls", "orcid": "0000-0001-7774-5025" }, { "affs": [ 15 ], "name": "Bart P C van de Warrenburg" }, { "affs": [ 16 ], "name": "Alexandra Durr", "orcid": "0000-0002-8921-7104" }, { "affs": [ 16 ], "name": "Alexis Brice", "orcid": "0000-0002-0941-3990" }, { "affs": [ 17 ], "name": "Thomas Klockgether" }, { "affs": [ 0 ], "name": "Olaf Riess", "orcid": "0000-0002-7011-1369" }, { "name": "EUROSCA Network" }, { "affs": [ 18 ], "name": "Thorsten Schmidt", "orcid": "0000-0002-1862-655X" } ], "bibtex": "https://research.draconitic.com/paper/ctngcmtmcd23m.bib", "cited_by": 0, "doi": "10.1007/s00401-026-03051-0", "fulltext_url": "https://europepmc.org/articles/PMC13722750", "id": "ctngcmtmcd23m", "issns": [ "0001-6322", "1432-0533" ], "landing_url": "https://europepmc.org/article/MED/42961534", "language": "eng", "licence": "CC-BY", "licence_label": "CC BY", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "heading", "Original Paper" ], [ "openalex", "2804|Genetic Neurodegenerative Diseases" ] ], "openalex": "W7224747134", "pdf_url": "https://europepmc.org/articles/PMC13722750?pdf=render", "pmcid": "PMC13722750", "pmid": "42961534", "published": "2026-10-30", "publisher": null, "ris": "https://research.draconitic.com/paper/ctngcmtmcd23m.ris", "sources": [ { "first_seen": "2026-11-02T03:21:21Z", "native_id": "MED:42961534", "source": "europepmc", "url": "https://europepmc.org/article/MED/42961534" }, { "first_seen": "2026-11-04T12:21:31Z", "native_id": "PMC13722750", "source": "pmc", "url": "https://doi.org/10.1007/s00401-026-03051-0" } ], "subjects": [ { "field": "biology", "origin": "openalex:2804|Genetic Neurodegenerative Diseases", "subfield": "neuroscience" } ], "title": "SNP rs11618521 modifies transcription factor NANOG-mediated expression of KPNA3 and the age at onset of spinocerebellar ataxia type 3.", "title_text": "SNP rs11618521 modifies transcription factor NANOG-mediated expression of KPNA3 and the age at onset of spinocerebellar ataxia type 3.", "type": "peer-reviewed", "updated_at": "2026-11-04T12:21:31Z", "url": "https://research.draconitic.com/paper/ctngcmtmcd23m", "venue": "Acta neuropathologica", "versions": [] }