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Resilience to Endoplasmic Reticulum Stress Mitigates Calcium-Dependent Membrane Hyperexcitability Underlying Late Disease Onset in Spinocerebellar Ataxia Type 6

ABSTRACT: 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 polyglutamine ataxia with late-onset cerebellar neurodegeneration. In a mouse model of SCA6, we identified a homeostatic response that engages the unfolded protein response early in disease. This protective response provided insight into endoplasmic reticulum (ER) stress-mediated cerebellar Purkinje neuron membrane hyperexcitability as a driver of disease. Age-dependent impairment of chaperone-mediated compensation for ER stress increased calcium-dependent Purkinje neuron membrane excitability. Redundant pathways of the unfolded protein response mediate this resilience to ER stress. ER stress-related decompensation applies also to other late-onset human cerebellar ataxia. 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE264100 | GEO | 2025/09/24

REPOSITORIES: GEO

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Project description:Spinocerebellar ataxia type 6 (SCA6) is a dominantly inherited neurodegenerative disease caused by an expansion of a CAG repeat encoding a polyglutamine (PolyQ) tract in the Cav2.1 voltage-gated calcium channel. Pathologically, it is characterized by selective degeneration of cerebellar Purkinje cells (PCs), which are a common target for PolyQ-induced toxicity among several different SCAs. Mutant Cav2.1 confers toxicity mainly through a toxic gain-of-function mechanism, but subcellular site of expanded Cav2.1 toxicity is controversial and it remains elusive whether SCA6 shares pathogenic cascades with other SCAs. To gain insight into these problems, we studied the cerebellar gene expression patterns of young Sca6 MPI 118Q/118Q knockin (KI) mice, which express mutant Cav2.1 from endogenous locus and faithfully models human SCA6. Comparison of transcriptional changes with those of Sca1 154Q/2Q mice, a faithful KI mouse model of SCA1, revealed that transcriptional signatures in the MPI 118Q/118Q were distinct from those of Sca1 154Q/2Q. Examination of temporal profiles of candidate genes showed that upregulation of those associated with microglial activation was initiated before PC degeneration was apparent and augmented as the disease progressed. Histological analysis of the MPI 118Q/118Q cerebellum confirmed the presence of Iba-1 positive activated microglia. Moreover, predominance of M1-like pro-inflammatory microglia was observed and was concomitant with the increased expression of pro-inflammatory cytokines. These results suggest that the unique transcriptional response, which highlights upregulation of neuroinflammatory genes possibly associated with lysosomal involvement, may play a pivotal role in the pathogenesis. Modulation of innate immune system could pave the way for slowing the progression of SCA6. We used MPI 118Q/118Q and MPI 11Q/11Q mice for Sca6 KI model at six weeks old. Statistical analysis of differently expressed genes was performed using the Linear Models for Microarray Data (limma) package in R/Bioconductor.

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Resilience to Endoplasmic Reticulum Stress Mitigates Calcium-Dependent Membrane Hyperexcitability Underlying Late Disease Onset in Spinocerebellar Ataxia Type 6

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