Spinocerebellar ataxia (SCA) type 51 is a neurodegenerative disease caused by CAG repeat expansions in exon 1 of the THAP11 gene. These repeats are translated into a glutamine-rich protein, THAP11-polyQ, which forms protein aggregates and exhibits toxicity in cell models; however, the underlying mechanism remains unclear. In this study, we generate transgenic Drosophila models expressing varying lengths of THAP11-polyQ using the UAS-GAL4 system and assess neurodegeneration through pathological and behavioral analyses. Our results demonstrate that expression of THAP11-polyQ in transgenic flies leads to progressive neuronal cell loss, locomotor deficiency, and reduced survival. RNA sequencing of patient-derived skin fibroblasts reveals significant enrichment of the PI3K–Akt–mTOR pathway, and electron microscopy of transgenic flies shows an increase in multilamellar bodies, suggesting involvement of autophagy in SCA51. Consequently, we treat the fly model with rapamycin, an mTOR inhibitor known to enhance autophagy. This treatment reduces toxic THAP11-polyQ protein aggregates, significantly alleviates neuronal degeneration, and improves locomotor function, consistent with the rescue effects observed upon overexpression of Atg8a. Overall, these findings suggest that the Drosophila model, which recapitulates the neurodegenerative features of SCA51, can be used to investigate pathogenic mechanisms and that rapamycin holds promising potential as a therapeutic approach for this disease.

Spinocerebellar ataxia type 51

PolyQ disease

THAP11 gene

Drosophila model

Rapamycin

© 2025 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Limited and Science Pressé