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Intracerebellar upregulation of Rheb(S16H) ameliorates motor dysfunction in mice with SCA2

Sehwan Kim1,2, Junwoo Park1, Hyemi Eo1, Gi Beom Lee1, Se Min Park1, Minsang Shin2,3, Seung Eun Lee4, Youngpyo Nam2, Sang Ryong Kim1,2
1 School of Life Science and Biotechnology, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Republic of Korea
2 Brain Science and Engineering Institute, Kyungpook National University, Daegu 41404, Republic of Korea
3 Department of Microbiology, School of Medicine, Kyungpook National University, Daegu 4.1944, Republic of Korea
4 esearch Animal Resource Center, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
Correspondence to: Youngpyo Nam: blackpyo2@knu.ac.kr, Sang Ryong Kim: srk75@knu.ac.kr,
DOI: 10.1038/s41401-025-01504-y
Received: 15 October 2024
Accepted: 4 February 2025
Advance online: 3 March 2025

Abstract

Cerebellar ataxia (CA) is characterized by impaired balance and coordination due to the loss of cerebellar neurons caused by various factors, and effective treatments are currently lacking. Recently, we observed reduced expression of signaling molecules in the mammalian target of rapamycin complex 1 (mTORC1) pathway in the cerebellum of mice with spinocerebellar ataxia type 2 (SCA2) compared with wild-type mice. To investigate the effects of mTORC1 upregulation on motor dysfunction in mice with SCA2, we administered an intracerebellar injection of adeno-associated virus serotype 1 carrying a constitutively active form of Ras homolog enriched in brain [Rheb(S16H)], which is an upstream activator of mTORC1. This treatment led to increased Rheb(S16H) expression in calbindin-D28K-positive Purkinje cells and increased levels of neurotrophic factors. Additionally, Rheb(S16H) upregulation reduced abnormal behaviors and protected Purkinje cells in mice with SCA2. Our findings suggest that upregulating Rheb(S16H) in the cerebellum may be a promising therapeutic strategy for hereditary CA.
Keywords: cerebellar ataxia; motor dysfunction; AAV1-Rheb(S16H); mTORC1; neurotrophic factor; neuroprotection

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