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

MPG-Autoren
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Hornburg,  Daniel
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

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Bader,  Jakob Maximilian
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

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Mann,  Matthias
Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society;

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Meissner,  Felix
Meissner, Felix / Experimental Systems Immunology, Max Planck Institute of Biochemistry, Max Planck Society;

Externe Ressourcen

https://doi.org/10.26508/lsa.201800054
(Ergänzendes Material)

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e201800070.full.pdf
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Zitation

Hartmann, H., Hornburg, D., Czuppa, M., Bader, J. M., Michaelsen, M., Farny, D., et al. (2018). Proteomics and C9orf72 neuropathology identify ribosomes as poly-GR/PR interactors driving toxicity. Life science alliance, 1(2): e201800070. doi:10.26508/lsa.201800070.


Zitierlink: https://hdl.handle.net/21.11116/0000-0003-153E-1
Zusammenfassung
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.