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ResearchIn-Press PreviewGeneticsNeuroscience Open Access | 10.1172/JCI178349

Mutant THAP11 causes cerebellar neurodegeneration and triggers TREM2-mediated microglial activation in mice

Eshu Ruan,1 Jingpan Lin,1 Zhao Chen,2 Qianai Sheng,1 Laiqiang Chen,1 Jiating He,1 Xuezhi Duan,1 Yiyang Qin,1 Tingting Xing,1 Sitong Yang,1 Mingtian Pan,1 Xiangyu Guo,1 Peng Yin,1 Xiao-Jiang Li,1 Hong Jiang,2 Shihua Li,1 and Su Yang1

1State Key Laboratory of Bioactive Molecules and Druggability Assessment, Gu, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China

2Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

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1State Key Laboratory of Bioactive Molecules and Druggability Assessment, Gu, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China

2Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

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1State Key Laboratory of Bioactive Molecules and Druggability Assessment, Gu, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China

2Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

Find articles by Chen, Z. in: PubMed | Google Scholar

1State Key Laboratory of Bioactive Molecules and Druggability Assessment, Gu, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China

2Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

Find articles by Sheng, Q. in: PubMed | Google Scholar

1State Key Laboratory of Bioactive Molecules and Druggability Assessment, Gu, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China

2Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

Find articles by Chen, L. in: PubMed | Google Scholar

1State Key Laboratory of Bioactive Molecules and Druggability Assessment, Gu, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China

2Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

Find articles by He, J. in: PubMed | Google Scholar

1State Key Laboratory of Bioactive Molecules and Druggability Assessment, Gu, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China

2Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

Find articles by Duan, X. in: PubMed | Google Scholar

1State Key Laboratory of Bioactive Molecules and Druggability Assessment, Gu, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China

2Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

Find articles by Qin, Y. in: PubMed | Google Scholar

1State Key Laboratory of Bioactive Molecules and Druggability Assessment, Gu, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China

2Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

Find articles by Xing, T. in: PubMed | Google Scholar

1State Key Laboratory of Bioactive Molecules and Druggability Assessment, Gu, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China

2Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

Find articles by Yang, S. in: PubMed | Google Scholar

1State Key Laboratory of Bioactive Molecules and Druggability Assessment, Gu, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China

2Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

Find articles by Pan, M. in: PubMed | Google Scholar

1State Key Laboratory of Bioactive Molecules and Druggability Assessment, Gu, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China

2Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

Find articles by Guo, X. in: PubMed | Google Scholar

1State Key Laboratory of Bioactive Molecules and Druggability Assessment, Gu, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China

2Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

Find articles by Yin, P. in: PubMed | Google Scholar

1State Key Laboratory of Bioactive Molecules and Druggability Assessment, Gu, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China

2Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

Find articles by Li, X. in: PubMed | Google Scholar

1State Key Laboratory of Bioactive Molecules and Druggability Assessment, Gu, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China

2Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

Find articles by Jiang, H. in: PubMed | Google Scholar

1State Key Laboratory of Bioactive Molecules and Druggability Assessment, Gu, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China

2Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

Find articles by Li, S. in: PubMed | Google Scholar |

1State Key Laboratory of Bioactive Molecules and Druggability Assessment, Gu, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China

2Department of Neurology, Xiangya Hospital, Central South University, Changsha, China

Find articles by Yang, S. in: PubMed | Google Scholar

Published June 3, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI178349.
Copyright © 2025, Ruan et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published June 3, 2025 - Version history
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Abstract

Abnormal expansions of CAG trinucleotide repeat within specific gene exons give rise to polyglutamine (polyQ) diseases, a family of inherited disorders characterized by late-onset neurodegeneration. Recently, a new type of polyQ disease was identified and named spinocerebellar ataxia 51 (SCA51). SCA51 is caused by polyQ expansion in THAP11, an essential transcription factor for brain development. The pathogenesis of SCA51, particularly how mutant THAP11 with polyQ expansion contributes to neuropathology, remains elusive. Our study of mouse and monkey brains revealed that THAP11 expression is subject to developmental regulation, showing enrichment in the cerebellum. However, knocking down endogenous THAP11 in adult mice does not affect neuronal survival. In contrast, expressing mutant THAP11 with polyQ expansion leads to pronounced protein aggregation, cerebellar neurodegeneration, and motor deficits, indicating that gain-of-function mechanisms are central to SCA51 pathogenesis. We discovered activated microglia expressing TREM2 in the cerebellum of a newly developed SCA51 knock-in mouse model. Mechanistically, mutant THAP11 enhances the transcription of TREM2, leading to its upregulation. The loss of TREM2 or depletion of microglia mitigates neurodegeneration induced by mutant THAP11. Our study offers the first mechanistic insights into the pathogenesis of SCA51, highlighting the role of TREM2-mediated microglial activation in SCA51 neuropathology.

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  • Version 1 (June 3, 2025): In-Press Preview
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