Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
Nat Commun. 2020 Oct 20;11(1):5304. doi: 10.1038/s41467-020-18949-w.
A missense mutation, S85C, in the MATR3 gene is a genetic cause for amyotrophic lateral sclerosis (ALS). It is unclear how the S85C mutation affects MATR3 function and contributes to disease. Here, we develop a mouse model that harbors the S85C mutation in the endogenous Matr3 locus using the CRISPR/Cas9 system. MATR3 S85C knock-in mice recapitulate behavioral and neuropathological features of early-stage ALS including motor impairment, muscle atrophy, neuromuscular junction defects, Purkinje cell degeneration and neuroinflammation in the cerebellum and spinal cord. Our neuropathology data reveals a loss of MATR3 S85C protein in the cell bodies of Purkinje cells and motor neurons, suggesting that a decrease in functional MATR3 levels or loss of MATR3 function contributes to neuronal defects. Our findings demonstrate that the MATR3 S85C mouse model mimics aspects of early-stage ALS and would be a promising tool for future basic and preclinical research.
MATR3 基因中的错义突变 S85C 是肌萎缩侧索硬化症（ALS）的遗传原因。目前尚不清楚 S85C 突变如何影响 MATR3 功能并导致疾病。在这里，我们使用 CRISPR/Cas9 系统在内源性 Matr3 基因座中开发了携带 S85C 突变的小鼠模型。MATR3 S85C 敲入小鼠重现了包括运动障碍、肌肉萎缩、运动神经元与肌纤维连接处缺陷、浦肯野细胞变性和小脑及脊髓神经炎症在内的 ALS 早期的行为和神经病理学特征。我们的神经病理学数据显示 S85C 蛋白在浦肯野细胞和运动神经元的细胞体中丢失，表明功能性 MATR3 水平降低或 MATR3 功能丧失导致神经元缺陷。我们的研究结果表明，MATR3 S85C 小鼠模型模拟了 ALS 早期的某些方面，将成为未来基础和临床前研究的有前途的工具。
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