Modulation of the Stress Granule Component Carhsp1 Mitigates Disease-Associated Deficits in Spinocerebellar Ataxia Type 3 Mouse Models.

BACKGROUND

Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine (polyQ) neurogenerative disorder that results from CAG trinucleotide repeat expansions in the ATXN3 gene, leading to toxic protein aggregate formation and cellular pathway dysfunction. The dysfunction of cellular pathways also correlates with stress responses, such as the formation of stress granules (SG). Recent research suggests that SG and their components contribute to polyglutamine disease pathogenesis.

METHODS

We combined the analysis of two mouse models for SCA3, data from RNA sequencing, and postmortem brain tissue samples.

RESULTS

This study intended to clarify the role of the SG component, calcium-regulated heat-stable protein 1 (CARHSP1), in SCA3. Among several SG components, CARHSP1 was found to be upregulated genetically in SCA3. The downregulation of Carhsp1 reduced the density of mutant protein aggregates, while enhancing motor function and alleviating neuropathological defects in SCA3 mouse models.

CONCLUSIONS

The findings indicate that modulating CARHSP1 and possible other SG components may provide a molecular target for therapeutics in SCA3, emphasizing the role of SG in polyQ disorders. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.