Resilience to Endoplasmic Reticulum Stress Mitigates Membrane Hyperexcitability Underlying Late Disease Onset in a Murine Model of SCA6.

OBJECTIVE: An enduring puzzle in many inherited neurological disorders is the late onset of symptoms despite expression of function-impairing mutant protein early in life. We examined the basis for onset of impairment in spinocerebellar ataxia type 6 (SCA6), a canonical late-onset neurodegenerative ataxia which results from a polyglutamine expansion in the voltage gated calcium channel, Cav2.1. METHODS: We performed serial transcriptome analysis with weighted gene correlation network analysis to investigate mechanisms for resilience in SCA6 mice that prevent onset of symptoms. We examined changes in membrane excitability that result in cerebellar Purkinje neuron spiking abnormalities through patch-clamp recordings of Purkinje neurons in acute brain slices. RESULTS: Using unbiased transcriptome analysis, we identified endoplasmic reticulum (ER) stress as a driver of disease. Using spatial transcriptome analysis, we identified Purkinje neuron specific changes in unfolded protein response (UPR) related pathways. Novel activation of a store-operated calcium current due to ER stress is the cause for Purkinje neuron spiking abnormalities in SCA6 mice. The impairments in Purkinje neuron spiking are unrelated to Cav2.1 ion-flux function. Redundant pathways of the UPR act through a HSP90-dependent mechanism to mitigate this ER stress. INTERPRETATION: 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.