Functional and structural basis of a hypermorphic TRPC3 variant

TL;DR

This study explains how a faulty TRPC3 protein causes cerebellar ataxia by staying open and leading to cell death, and identifies a potential drug target to treat it.

Contribution

The paper reveals the structural and functional basis of a TRPC3 mutation in ataxia and identifies a new druggable site for treatment.

Findings

A TRPC3 mutation stabilizes the channel in an open state, causing calcium-dependent cell death in cerebellar neurons.

Cryo-EM and simulations show the structural changes in the TRPC3 variant and reveal an allosteric inhibitory site.

Expressing a calcium pump in Purkinje cells improves cell viability, and the TRPC3 variant causes neurodegeneration in C. elegans.

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.

Structural snapshots capture an ataxia-linked overactive ion channel in its open state and reveal a druggable site for inhibition.

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