Rapamycin alleviates neurodegeneration in a <i>Drosophila</i> model of spinocerebellar ataxia type 51

Cuijie Wei; Taoyun Ji; Jin Xu; Yilei Zheng; Fuze Zheng; Suxia Wang; Chao Gao; Yalan Wan; Zhenyu Li; Jianwen Deng; Hui Xiong

doi:10.1016/j.jgg.2025.08.010

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Rapamycin alleviates neurodegeneration in a Drosophila model of spinocerebellar ataxia type 51

doi: 10.1016/j.jgg.2025.08.010

a. Department of Neurology, Children's Medical Center, Peking University First Hospital, Beijing 102627, China;
b. Center of Ultrastructural Pathology, Lab of Electron Microscopy, Peking University First Hospital, Beijing 100034, China;
c. Department of Neurology, Peking University First Hospital, Beijing 100034, China;
d. Rare Diseases Medical Center, Peking University First Hospital, Beijing 100034, China;
e. Beijing Key Laboratory of Neurovascular Disease Discovery, Beijing 100034, China;
f. Department of Neurology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China

Funds:

Clinical Medicine Plus X-Young Scholars Project of Peking University (PKU2025PKULCXQ026)

High Quality Clinical Research Project of Peking University First Hospital, No. 2022CR69), and Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases (BZ0317).

National High Level Hospital Clinical Research Funding (Interdepartmental Research Project of Peking University First Hospital, No. 2023IR51

This work is financially supported by the National Natural Science Foundations of China (82402177, 82171846, 82422025, 82471430)

Received Date: 2025-02-25
Accepted Date: 2025-08-26
Rev Recd Date: 2025-08-23

Available Online: 2025-08-30

Abstract

Abstract

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

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References

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