Functional and structural basis of a hypermorphic TRPC3 variant

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Cerebellar ataxias involve motor coordination deficits due to cerebellar neuronal dysfunction.
• The precise mechanisms driving cerebellar neurodegeneration in these conditions are not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying TRPC3-associated cerebellar ataxia.
• To identify potential therapeutic targets for restoring neuronal function.

Main Methods:

• Investigated a gain-of-function TRPC3 mutation using cell-based assays and structural biology techniques (cryo-electron microscopy).
• Utilized molecular simulations and transgenic *Caenorhabditis elegans* models.
• Assessed the impact of restoring calcium homeostasis via Purkinje cell calcium pumps.

Main Results:

• A specific TRPC3 mutation stabilizes the channel's open state, resisting inhibition and causing calcium-dependent cell death.
• Transgenic expression of the mutated TRPC3 induced neurodegeneration in *C. elegans*, confirming pathogenicity.
• Cryo-EM and simulations revealed the structural basis for channel stabilization and identified a druggable allosteric binding site.

Conclusions:

• The study explains cerebellar neuron vulnerability in TRPC3-associated ataxias.
• Targeting the identified allosteric site on TRPC3 presents a potential therapeutic avenue.