SNP rs11618521 modifies transcription factor NANOG-mediated expression of KPNA3 and the age at onset of spinocerebellar ataxia type 3

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.

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Journal
Acta Neuropathologica
Published
2026-10-30
DOI
https://doi.org/10.1007/s00401-026-03051-0
Primary Topic
Genetic Neurodegenerative Diseases
Type
article
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article

SNP rs11618521 modifies transcription factor NANOG-mediated expression of KPNA3 and the age at onset of spinocerebellar ataxia type 3

Mario Cornejo‐Olivas, Roy Zaltzman, Marcondes C. França, Gunnar Blumenstock et al.
Acta Neuropathologica
Genetic Neurodegenerative Diseases
article

SNP rs11618521 modifies transcription factor NANOG-mediated expression of KPNA3 and the age at onset of spinocerebellar ataxia type 3

Mario Cornejo‐Olivas, Roy Zaltzman, Marcondes C. França, Gunnar Blumenstock, Bart P.C. van de Warrenburg, Thorsten Schmidt, Jonasz Jeremiasz Weber, Laura Bannach Jardim, Alexandra Dürr, Alexis Brice, Miriam Christina Dieterle, Thomas Klockgether, Priscila Pereira Sena, Fubo Cheng, Manuel Pascal Wanner, Hezhou Han, Jaqueline Jung, Olaf Rieß, Ludger J. Schöls, Maria Luiza Saraiva Pereira, Wenxu Zheng, Florian Fath, Peter Bauer, Carlos R. Gordon, Leah Czisch, Junbo Zhou, Pengfei Qi, The EUROSCA Network, Carolina Alexandra Licia Schroeder
article en

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.

Acta NeuropathologicaVol. 152(1)
Centre National de la Recherche Scientifique (FR), Universidade Federal do Rio Grande do Sul (BR), Radboud University Nijmegen (NL), Inserm (FR), Tel Aviv University (IL), Universidade Estadual de Campinas (UNICAMP) (BR), Universidad Científica del Sur (PE), Tel Aviv Sourasky Medical Center (IL), German Center for Neurodegenerative Diseases (DE), Meir Medical Center (IL), Radboud University Medical Center (NL), Sorbonne Université (FR), Hospital de Clínicas de Porto Alegre (BR), Assistance Publique – Hôpitaux de Paris (FR), Pitié-Salpêtrière Hospital (FR), Centogene (Germany) (DE), Hertie Institute for Clinical Brain Research (DE), Institut du Cerveau (FR), Instituto Nacional de Ciencias Neurológicas (PE), Donders Institute for Brain, Cognition and Behaviour (NL), Pomeranian Medical University (PL), University of Tübingen (DE), Ruhr University Bochum (DE)
E-Rare, European Commission, Deutscher Akademischer Austauschdienst, Deutsche Forschungsgemeinschaft, Eberhard Karls Universität Tübingen, Bundesministerium für Bildung und Forschung, Conselho Nacional de Desenvolvimento Científico e Tecnológico, China Scholarship Council, Consejo Nacional de Ciencia, Tecnología e Innovación Tecnológica, Universitätsklinikum Tübingen, Ciência sem Fronteiras
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