Faculty, Staff and Student Publications

Language

English

Publication Date

3-27-2026

Journal

Science Advances

DOI

10.1126/sciadv.aec9284

PMID

41880503

PMCID

PMC13015894

PubMedCentral® Posted Date

3-25-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Cerebellar ataxias are characterized by impaired motor coordination resulting from neuronal dysfunction within the cerebellum. The mechanisms underlying this pathology and its cerebellar-specific neurodegeneration remain unknown. We uncover how a gain-of-function canonical transient receptor potential member 3 (TRPC3) mutation, coupled with a cerebellum-specific isoform, stabilizes the channel’s open state, resists the leading inhibitor Pyr3, and drives calcium-dependent cell death. Restoring calcium homeostasis by expressing a Purkinje cell calcium pump improves cell viability. Transgenic expression of the TRPC3 hypermorphic variant in Caenorhabditis elegans induces neurodegeneration, confirming its pathogenicity across species. Cryo–electron microscopy and molecular simulations reveal the structural basis for the stabilization of the cerebellar-specific TRPC3 variant in its open state and uncover a druggable allosteric inhibitory binding site. These findings provide an explanation for the vulnerability of cerebellar neurons in TRPC3-associated ataxias and highlight a site for therapeutic intervention.

Keywords

TRPC Cation Channels, Animals, Caenorhabditis elegans, Humans, Calcium, Mutation, Cryoelectron Microscopy, Purkinje Cells, Cerebellum, Animals, Genetically Modified

Published Open-Access

yes

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