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Hartmann, Hannelore; Hornburg, Daniel; Czuppa, Mareike; Bader, Jakob; Michaelsen, Meike; Farny, Daniel; Arzberger, Thomas; Mann, Matthias; Meissner, Felix; Edbauer, Dieter (2018): Proteomics and C9orf72 neuropathology identify ribosomes as poly-GR/PR interactors driving toxicity. In: Life Science Alliance, Vol. 1, No. 2, e201800070
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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 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.