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

• DOI: 10.1093/brain/awaa076
• Publication Date: 2020-02-27T12:25:19Z
• Authors: Xue Zhang; Fengchao Wang; Yi Hu; Runze Chen; Dawei Meng; Liang Guo; Hailong Lv; Jisong Guan; Yichang Jia
• Keywords: Gene knockin; Knockout mouse; Stress granule; Animal model

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 protein disrupts processing in vivo pathogenesis is unknown. Here we establish FUS ALS mutation, p.R521C, knock-in mouse model that carries impaired motor ability late-onset neuron loss. In disease-susceptible neurons, induces mislocalization into granules upregulation ubiquitin, two hallmarks disease pathology. Additionally, aggravates performance decline the mouse. By using two-photon imaging TIA1-EGFP transduced animals, document more intensely TIA1-EGFP-positive formed hours but cleared weeks after challenge neurons cortex. Moreover, with severe misprocessing die days challenge. Therefore, argue pathogenic ALS, provide here sound for further mechanistic study.