Resilience to Endoplasmic Reticulum Stress Mitigates Membrane Hyperexcitability Underlying Late Disease Onset in a Murine Model of <scp>SCA6</scp>
Our studies support a model whereby proteotoxicity from misfolded mutant Cav2.1 is mitigated by a HSP90-dependent UPR, and age-related breakdown of this response causes motor dysfunction and aberrant Purkinje neuron spiking. These studies elucidate a mechanism of resilience connecting aberrant proteostasis and calcium-dependent intrinsic membrane hyperexcitability to explain delayed disease onset more widely in age-dependent neurodegenerative disease. ANN NEUROL 2026;99:502-522.
Authors
- Geneviève Konopka (ORCID: https://orcid.org/0000-0002-3363-7302)
- Maureen Dunn (ORCID: https://orcid.org/0000-0003-2689-8325)
- Praveen Kumar (ORCID: https://orcid.org/0000-0002-8890-9969)
- Allan‐Hermann Pool (ORCID: https://orcid.org/0000-0002-0811-9861)
- Deborah M. Jones
- Vikram G. Shakkottai (ORCID: https://orcid.org/0000-0003-2742-6469)
- Ashwinikumar Kulkarni (ORCID: https://orcid.org/0000-0003-0951-2427)
- Satoshi Ishishita (ORCID: https://orcid.org/0000-0003-4440-4878)
- Min Fu (ORCID: https://orcid.org/0000-0002-2038-9039)
- Haoran Huang (ORCID: https://orcid.org/0000-0001-6125-5996)
- Taylor L. Charron
Institutions
- University of California, Los Angeles (US)
- Southwestern Medical Center (US)
- The Ohio State University (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Annals of Neurology
- Published
- 2025-09-24
- DOI
- https://doi.org/10.1002/ana.78042
- Primary Topic
- Genetic Neurodegenerative Diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Institutes of Health