期刊
LIFE SCIENCE ALLIANCE
卷 1, 期 2, 页码 -出版社
LIFE SCIENCE ALLIANCE LLC
DOI: 10.26508/lsa.201800070
关键词
-
类别
资金
- Hans und Ilse Breuer Foundation
- Munich Cluster of Systems Neurology
- NOMIS Foundation
- European Community [SyG-318987, 259867, 617198]
Frontotemporal dementia and amyotrophic lateral sclerosis patients with C9orf72 mutation show cytoplasmic poly-GR and poly-PR aggregates. Short poly-(Gly-Arg) and poly-(Pro-Arg) (poly-GR/PR) repeats localizing to the nucleolus are toxic in various model systems, but no interactors have been validated in patients. Here, the neuronal interactomes of cytoplasmic GFP-(GR)(149) and nucleolar (PR)(175)-GFP revealed overlapping RNA-binding proteins, including components of stress granules, nucleoli, and ribosomes. Overexpressing the poly-GR/PR interactors STAU1/2 and YBX1 caused cytoplasmic aggregation of poly-GR/PR in large stress granule-like structures, whereas NPM1 recruited poly-GR into the nucleolus. Poly-PR expression reduced ribosome levels and translation consistent with reduction of synaptic proteins detected by proteomics. Surprisingly, truncated GFP-(GR)(53), but not GFP-(GR)(149), localized to the nucleolus and reduced ribosome levels and translation similar to poly-PR, suggesting that impaired ribosome biogenesis may be driving the acute toxicity observed in vitro. In patients, only ribosomes and STAU2 co-aggregated with poly-GR/PR. Partial sequestration of ribosomesmay chronically impair protein synthesis even in the absence of nucleolar localization and contribute to pathogenesis.
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