Cerebellar ataxias are characterized by impaired motor coordination resulting from neuronal dysfunction or degeneration within the cerebellum. The canonical transient receptor potential type 3 (TRPC3) ion channel has been implicated in the development of various disorders, including cerebellar ataxia. A gain-of-function mutation in the TRPC3 ion channel results in degeneration of Purkinje and type II unipolar brush cells of the cerebellum, leading to ataxia. The mechanisms underlying this pathology and its associated cerebellar-specific neurodegeneration remain unknown. Likewise, therapeutic strategies targeting the development and progression of cerebellar ataxia have been greatly limited due to a lack of mechanistic insight. Here, using electrophysiology and Ca 2+ imaging, we uncover how this TRPC3 mutation, coupled with a naturally occurring 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 C. elegans eliminates TRPC3-mediated behavioral responses observed in wild-type TRPC3 transgenic worms and induces neurodegeneration, recapitulating the pathology characteristic of cerebellar ataxia, confirming its pathogenicity and demonstrating conservation of the disease mechanism across species. Cryo-EM imaging reveals the structural basis for the stabilization of the cerebellar-specific hypermorphic TRPC3 variant in its open state, while molecular dynamics simulations confirm a low-energy barrier at the hydrophobic gate, driving aberrant channel activity. The cryo-EM structure of the hypermorphic variant in the presence of an antagonist uncovers a unique druggable allosteric inhibitory binding site. Together, these findings provide a mechanistic framework for TRPC3-driven cerebellar ataxia, explain the selective vulnerability of cerebellar neurons, and highlight new avenues for therapeutic intervention.
Bell et al. (Sun,) studied this question.