In vivo stress granule misprocessing evidenced in a FUS knock-in ALS mouse model

作者：Xue Zhang, Fengchao Wang, Yi Hu, Runze Chen, Dawei Meng, Liang Guo, Hailong Lv, Ji‐Song Guan, Yichang Jia · 发表于：Brain · 年份：2020 · DOI：10.1093/brain/awaa076 · 被引用次数：76 · 研究领域：Amyotrophic Lateral Sclerosis Research、Prion Diseases and Protein Misfolding、Neurogenetic and Muscular Disorders Research

Many RNA-binding proteins, including TDP-43, FUS, and TIA1, are stress granule components, dysfunction of which causes amyotrophic lateral sclerosis (ALS). However, whether a mutant RNA-binding protein disrupts stress granule processing in vivo in pathogenesis is unknown. Here we establish a FUS ALS mutation, p.R521C, knock-in mouse model that carries impaired motor ability and late-onset motor neuron loss. In disease-susceptible neurons, stress induces mislocalization of mutant FUS into stress granules and upregulation of ubiquitin, two hallmarks of disease pathology. Additionally, stress aggravates motor performance decline in the mutant mouse. By using two-photon imaging in TIA1-EGFP transduced animals, we document more intensely TIA1-EGFP-positive granules formed hours but cleared weeks after stress challenge in neurons in the mutant cortex. Moreover, neurons with severe granule misprocessing die days after stress challenge. Therefore, we argue that stress granule misprocessing is pathogenic in ALS, and the model we provide here is sound for further disease mechanistic study.