Adipose-Derived Mesenchymal Stem Cells Improve Motor Function and Reduce Neuroinflammation and Mutant Ataxin-3 Protein Levels in SCA3 Mice.

The CAG expansion in the ataxin-3 (ATXN3) protein is the underlying cause of Spinocerebellar Ataxia Type 3 (SCA3), a polyglutamine disease. The aggregation of mutant ATXN3 protein is hypothesized to contribute to neuronal dysfunction, neurodegeneration, or neuroinflammation. Mesenchymal stem cells have pleiotropic therapeutic properties, and adipose-derived mesenchymal stem cells (ADMSC) have been shown to be safe and well-tolerated in SCA3 patients. In this study, we evaluated the therapeutic effects of ADMSC in SCA3 mice. In a mouse model of SCA3, the Purkinje-cell-specific L7 promoter drives the expression of a truncated form of human ataxin-3 with 69 glutamine repeats. SCA3 mice exhibited cerebellar Purkinje cell degeneration, reduced myelination, and increased gliosis; pathological features also observed in SCA3 patients. SCA3 mice received repeated intravenous administrations of ADMSC, and efficacy was assessed by rotarod performance, molecular and pathological changes, and serum neurofilament light chain (NfL) levels. ADMSC-treated SCA3 mice showed significant improvements in rotarod performance, a reduction in accumulated toxic mutant ATXN3-69Q protein in Purkinje cells, decreased demyelination, and alleviation of neuroinflammatory and systemic inflammatory responses during disease progression. Furthermore, NfL levels, a potential biomarker for SCA3 disease progression, were inversely correlated with the rotarod performance. Based on these findings, we conclude that ADMSC enhance motor function in SCA3 mice by reducing neuroinflammation, demyelination and aggregated mutant ataxin-3 protein levels in Purkinje cells. ADMSC have the potential to serve as a disease-modifying therapy for SCA3 patients.