RT Journal Article
SR Electronic
T1 Proteomics and <em>C9orf72</em> neuropathology identify ribosomes as poly-GR/PR interactors driving toxicity
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201800070
DO 10.26508/lsa.201800070
VO 1
IS 2
A1 Hannelore Hartmann
A1 Daniel Hornburg
A1 Mareike Czuppa
A1 Jakob Bader
A1 Meike Michaelsen
A1 Daniel Farny
A1 Thomas Arzberger
A1 Matthias Mann
A1 Felix Meissner
A1 Dieter Edbauer
YR 2018
UL https://www.life-science-alliance.org/content/1/2/e201800070.abstract
AB 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 ribosomes may chronically impair protein synthesis even in the absence of nucleolar localization and contribute to pathogenesis.