Ruan Eshu, Lin Jingpan, Chen Zhao, Sheng Qianai, Chen Laiqiang, He Jiating, Duan Xuezhi, Qin Yiyang, Xing Tingting, Yang Sitong, Pan Mingtian, Guo Xiangyu, Yin Peng, Li Xiao-Jiang, Jiang Hong, Li Shihua, Yang Su
State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Provincial Key Laboratory of Non-human Primate Research, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, and.
Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou, China.
J Clin Invest. 2025 Jun 3;135(14). doi: 10.1172/JCI178349. eCollection 2025 Jul 15.
Abnormal expansions of the 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 THAP domain containing 11 (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 did not affect neuronal survival. In contrast, expressing mutant THAP11 with polyQ expansion led 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 triggering receptor expressed on myeloid cells 2 (TREM2) in the cerebellum of a newly developed SCA51 knockin mouse model. Mechanistically, mutant THAP11 enhanced the transcription of TREM2, leading to its upregulation. The loss of TREM2 or depletion of microglia mitigated neurodegeneration induced by mutant THAP11. Our study offers the first mechanistic insights to our knowledge into the pathogenesis of SCA51, highlighting the role of TREM2-mediated microglial activation in SCA51 neuropathology.
特定基因外显子内CAG三核苷酸重复序列的异常扩增会引发多聚谷氨酰胺（polyQ）疾病，这是一类以迟发性神经退行性病变为特征的遗传性疾病。最近，一种新型的polyQ疾病被鉴定出来，并命名为脊髓小脑共济失调51型（SCA51）。SCA51是由含THAP结构域11（THAP11）中的polyQ扩增引起的，THAP11是大脑发育所必需的转录因子。SCA51的发病机制，尤其是polyQ扩增的突变型THAP11如何导致神经病理学改变，仍然不清楚。我们对小鼠和猴脑的研究表明，THAP11的表达受发育调控，在小脑中表达丰富。然而，在成年小鼠中敲低内源性THAP11并不影响神经元存活。相反，表达具有polyQ扩增的突变型THAP11会导致明显的蛋白质聚集、小脑神经退行性变和运动缺陷，这表明功能获得机制是SCA51发病机制的核心。我们在新建立的SCA51基因敲入小鼠模型的小脑中发现了表达髓系细胞触发受体2（TREM2）的活化小胶质细胞。从机制上讲，突变型THAP11增强了TREM2的转录，导致其上调。TREM2的缺失或小胶质细胞的清除减轻了突变型THAP11诱导的神经退行性变。据我们所知，我们的研究首次对SCA51的发病机制提供了机制性见解，突出了TREM2介导的小胶质细胞活化在SCA51神经病理学中的作用。
