Autosomal recessive spinocerebellar ataxia type 10 (SCAR10) is a rare, slowly progressive neurodegenerative disorder characterised by ataxia, cerebellar atrophy, and oculomotor abnormalities, caused by variants in the ANO10 (anoctamin 10) gene. While ANO10-mediated calcium dysregulation in Purkinje cells has been proposed to cause SCAR10, the precise pathogenic mechanism remains unclear. To investigate cellular responses to ANO10 deficiency, four ANO10-mutant neuronal cell lines – a knockout and three lines harbouring recurrent SCAR10-associated pathogenic variants – were engineered using CRISPR/Cas9 editing, expanded by clonal isolation, and characterised by flow cytometry. Mass spectrometry-based proteomics identified differentially expressed proteins between control and mutant lines, and bioinformatic analyses uncovered candidate pathways involved in disease pathogenesis. Comparative proteomic analysis revealed disruptions in synaptic function, cell cycle regulation, extracellular matrix remodelling, and immune homeostasis as candidate pathways potentially contributing to SCAR10 pathogenesis. All four processes are functionally linked to calcium signalling, aligning with previous reports implicating abnormal calcium homeostasis in spinocerebellar ataxias. This study provides, for the first time, insights into the proteomic profile of SCAR10 using cell-based models and highlights specific molecules and pathways that may contribute to disease pathogenesis. These findings offer a foundation for further investigation and experimental validation, with potential implications for the development of targeted therapeutic approaches.
Chrysanthou et al. (Wed,) studied this question.