Proteomics and C9orf72 neuropathology identify ribosomes as poly-GR/PR interactors driving toxicity.

ABSTRACT: 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 consist

SUBMITTER: Hartmann H 

PROVIDER: S-EPMC6238541 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature