近日，美国加州大学教授X. William Yang及其团队的最新研究探明了不同的错配修复复合体基因设置神经元CAG-重复扩增率，驱动HD小鼠的选择性发病。2025年2月11日出版的《细胞》发表了这项成果。

该课题组人员对具有140个遗传CAG重复序列（Q140）的突变型亨廷顿蛋白（mHtt）小鼠进行了9个HD全基因组关联研究(GWAS)/MMR基因的遗传检测。强烈（Msh3和Pms1）或中度（Msh2和Mlh1）敲除编码不同MMR复合物的基因（KO），可以挽救纹状体中棘神经元（MSNs）早发和皮质神经元晚发的表型：体细胞CAG-重复扩增、转录病和mHtt聚集。Msh3缺乏可改善Q140神经元的开放染色质失调。

从机制上讲，MMR突变体显著降低或停止了MMR细胞中mHtt模态-CAG-重复扩增的快速线性速率（8.8次/月）。Msh3或Pms1的缺乏使体细胞MSN CAG长度保持在150以下，从而阻止mHtt聚集。重要的是，Msh3缺乏纠正了HD小鼠的突触、星形细胞和运动缺陷。它们、Msh3和Pms1在HD易感神经元中驱动快速体细胞mHtt CAG扩增率，从而在体内引发重复长度/阈值依赖性、选择性和进行性发病机制。

据悉，亨廷顿氏病（HD）修饰因子包括错配修复（MMR）基因，但它们与神经元发病机制的联系尚不清楚。

附：英文原文

Title: Distinct mismatch-repair complex genes set neuronal CAG-repeat expansion rate to drive selective pathogenesis in HD mice

Author: Nan Wang, Shasha Zhang, Peter Langfelder, Lalini Ramanathan, Fuying Gao, Mary Plascencia, Raymond Vaca, Xiaofeng Gu, Linna Deng, Leonardo E. Dionisio, Ha Vu, Emily Maciejewski, Jason Ernst, Brinda C. Prasad, Thomas F. Vogt, Steve Horvath, Jeffrey S. Aaronson, Jim Rosinski, X. William Yang

Issue&Volume: 2025-02-11

Abstract: Huntington’s disease (HD) modifiers include mismatch-repair (MMR) genes, but their connections to neuronal pathogenesis remain unclear. Here, we genetically tested 9 HD genome-wide association study (GWAS)/MMR genes in mutant Huntingtin (mHtt) mice with 140 inherited CAG repeats (Q140). Knockout (KO) of genes encoding a distinct MMR complex either strongly (Msh3 and Pms1) or moderately (Msh2 and Mlh1) rescues phenotypes with early onset in striatal medium-spiny neurons (MSNs) and late onset in the cortical neurons: somatic CAG-repeat expansion, transcriptionopathy, and mHtt aggregation. Msh3 deficiency ameliorates open-chromatin dysregulation in Q140 neurons. Mechanistically, the fast linear rate of mHtt modal-CAG-repeat expansion in MSNs (8.8 repeats/month) is drastically reduced or stopped by MMR mutants. Msh3 or Pms1 deficiency prevents mHtt aggregation by keeping somatic MSN CAG length below 150. Importantly, Msh3 deficiency corrects synaptic, astrocytic, and locomotor defects in HD mice. Thus, Msh3 and Pms1 drive fast somatic mHtt CAG-expansion rates in HD-vulnerable neurons to elicit repeat-length/threshold-dependent, selective, and progressive pathogenesis in vivo.

DOI: 10.1016/j.cell.2025.01.031

Source: https://www.cell.com/cell/abstract/S0092-8674(25)00100-X