In vitro study: generation of a non-invasive patient-derived neurodegenerative model for spinocerebellar ataxia 6

Abstract

Background: Spinocerebellar ataxia (SCA) is a rare neurodegenerative disorder defined by genetic mutations that cause gait disturbances and impaired motor coordination. Among its subtypes, SCA6 arises from mutations in the CACNA1A gene that disrupt calcium signaling and lead to neuronal cell death. Despite extensive research, no effective treatments are available. Methods: In this study, we established a non？invasive, patient？derived induced pluripotent stem cell (iPSC) model to investigate the pathological mechanisms of SCA6. Urinary cells collected from an SCA6 patient were successfully reprogrammed into iPSCs, as confirmed by alkaline phosphatase staining and the expression of key pluripotency markers. Results: These iPSCs were subsequently differentiated into cerebellar organoids that progressively exhibited characteristic cerebellar neuron markers. Phenotypic analysis revealed significant abnormalities in SCA6？derived cerebellar neurons, including reduced organoid size, impaired neurite formation, and decreased expression of KIRREL, a marker of Purkinje cells. Conclusion: These findings indicate that our iPSC？derived cerebellar organoid model effectively recapitulates key pathological features of SCA6, providing a valuable platform for elucidating the cellular mechanisms underlying this disorder and for developing targeted therapeutic approaches.