期刊
ISCIENCE
卷 25, 期 3, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.isci.2022.103900
关键词
-
资金
- NIH [R35GM128772, F31NS120512]
- WUSTL uSTAR Award
- Target ALS Springboard Award
- Frick Foundation for ALS Research Award
- ALS Association [20-IIA-529, 18-IIA-408]
- Office of Research Infrastructure Programs (ORIP), National Institutes of Health Office of the Director [OD021629]
We developed a yeast model of MATR3 proteotoxicity and aggregation, and found that MATR3 is toxic and forms nuclear condensates in yeast. Disease-associated mutations impair condensate dynamics and morphology. Hsp104 variants can reverse aberrant phase separation of various RBPs and counter MATR3 toxicity. Our yeast model can be used to screen for modulators of MATR3 misfolding.
Matrin-3 (MATR3) is a DNA- and RNA-binding protein implicated in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and distal myopathy. Here, we report the development of a yeast model of MATR3 proteotoxicity and aggregation. MATR3 is toxic and forms dynamic shell-like nuclear condensates in yeast. Disease-associated mutations in MATR3 impair condensate dynamics and disrupt condensate morphology. MATR3 toxicity is largely driven by its RNA-recognitions motifs (RPMs). Further, deletion of one or both RRMs drives coalescence of these condensates. Aberrant phase separation of several different RBPs underpins ALS/FTD, and we have engineered Hsp104 variants to reverse this misfolding. Here, we demonstrate that these same variants also counter MATR3 toxicity. We suggest that these Hsp104 variants which rescue MATR3, TDP-43, and FUS toxicity night be employed against a range of ALS/FTD-associated proteins. We anticipate that our yeast model could be a useful platform to screen for modulators of MATR3 misfolding.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据