期刊
CELL REPORTS
卷 27, 期 4, 页码 1133-+出版社
CELL PRESS
DOI: 10.1016/j.celrep.2019.03.093
关键词
-
类别
资金
- NIH, General Medical Sciences (GM) [T-32-GM00731.5]
- National Institute for Neurological Disorders and Stroke (NINDS) [R01-NS097542, R01-NS094678]
- National Institute on Aging (NIA) [P30 AG053760]
- University of Michigan Protein Folding Disease Initiative
- Fred A. and Barbara M. Erb Family Foundation [G020562]
The majority of individuals with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) exhibit neuronal cytoplasmic inclusions rich in the RNA binding protein TDP43. Even so, the relation between the RNA binding properties of TDP43 and neurodegeneration remains obscure. Here, we show that engineered mutations disrupting a salt bridge between the RNA recognition motifs of TDP43 interfere with RNA binding and eliminate the recognition of native TDP43 substrates. The same mutations dramatically destabilize TDP43, alter its subcellular localization, and abrogate TDP43-dependent neurodegeneration. Worms harboring homologous TDP-1 mutations phenocopy knockout strains, confirming the necessity of salt bridge residues for TDP43 function. Moreover, the accumulation of functional TDP43, but not RNA binding-deficient variants, disproportionately affects transcripts encoding ribosome and oxidative phosphorylation components. These studies demonstrate the significance of the salt bridge in sustaining TDP43 stability and RNA binding properties, factors that are crucial for neurodegeneration arising from TDP43 deposition in ALS and FTD.
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