Longitudinal Dynamics of Polyglutamine-Expanded ATXN3 in Biofluids of Spinocerebellar Ataxia Type 3

Authors

• Jordan Bartfield, Mayo Clinic Graduate School of Biomedical Sciences
• Lukasz Milanowski, Mayo Clinic in Jacksonville, Florida
• Karen R. Jansen-West, Mayo Clinic Graduate School of Biomedical Sciences
• Rana Hanna Al-Shaikh, Mayo Clinic in Jacksonville, Florida
• Tomasz Chmiela, Mayo Clinic in Jacksonville, Florida
• Tania F. Gendron, Mayo Clinic Graduate School of Biomedical Sciences
• Judith A. Dunmore, Mayo Clinic Graduate School of Biomedical Sciences
• Sorina Gorcenco, Neurologi, Lund
• Andreas Puschmann, Neurologi, Lund
• João Lemos, Centro Hospitalar e Universitário de Coimbra
• Cristina Januário, Centro Hospitalar e Universitário de Coimbra
• Mark S. LeDoux, University of Memphis
• Joseph H. Friedman, The Warren Alpert Medical School
• Osamu Onodera, Brain Research Institute
• Ikuko Aiba, National Hospital Organization Higashi Nagoya National Hospital
• Ronald F. Pfeiffer, OHSU School of Medicine
• Henry L. Paulson, University of Michigan Medical School
• Hayley S. McLoughlin, University of Michigan Medical School
• Jaroslaw Dulski, Mayo Clinic in Jacksonville, Florida
• Jaroslaw Slawek, Gdanski Uniwersytet Medyczny
• Helio A.G. Teive, Universidade Federal do Parana
• Alexandra E. Soto-Piña, Universidad Autónoma del Estado del México, Facultad de Medicina
• Ryan J. Uitti, Mayo Clinic in Jacksonville, Florida
• Audrey Strongosky, Mayo Clinic in Jacksonville, Florida
• Leonard Petrucelli, Mayo Clinic Graduate School of Biomedical Sciences
• Mercedes Prudencio, Mayo Clinic Graduate School of Biomedical Sciences
• Zbigniew K. Wszolek, Mayo Clinic in Jacksonville, Florida

Abstract

Background: Spinocerebellar ataxia type 3 (SCA3), the most common autosomal dominant ataxia, is driven by the accumulation of polyglutamine-expanded (polyQ) ATXN3 proteins. While promising as biomarkers, their longitudinal trajectories across multiple biofluids remain poorly defined. Objectives: To quantify polyQ ATXN3 levels in cerebrospinal fluid (CSF), plasma, and urine within a comprehensive cohort, utilizing serial measurements to map protein dynamics. Methods: We employed a validated immunoassay to quantify polyQ ATXN3 in 97 symptomatic and 13 presymptomatic SCA3 patients, correlating levels with clinical features, ancestry, disease status, and longitudinal progression. Results: Asian participants exhibited lower plasma but elevated urinary polyQ ATXN3 levels relative to other ancestries. While CSF levels were higher in symptomatic patients at baseline, they showed a significant longitudinal decline. Conclusions: PolyQ ATXN3 is a viable multi-biofluid biomarker. Declining CSF levels likely reflect neurodegeneration, supporting its role in tracking progression and emphasizing the need for ancestry-based adjustment in trials. © 2026 International Parkinson and Movement Disorder Society.

Publication Title

Movement Disorders

Recommended Citation

Bartfield, J., Milanowski, L., Jansen-West, K., Hanna Al-Shaikh, R., Chmiela, T., Gendron, T., Dunmore, J., Gorcenco, S., Puschmann, A., Lemos, J., Januário, C., LeDoux, M., Friedman, J., Onodera, O., Aiba, I., Pfeiffer, R., Paulson, H., McLoughlin, H., Dulski, J., Slawek, J., Teive, H., Soto-Piña, A., Uitti, R., Strongosky, A., Petrucelli, L., Prudencio, M., & Wszolek, Z. (2026). Longitudinal Dynamics of Polyglutamine-Expanded ATXN3 in Biofluids of Spinocerebellar Ataxia Type 3. Movement Disorders https://doi.org/10.1002/mds.70411