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

Hartmann, H., Hornburg, D., Czuppa, M., Bader, J., 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.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-153E-1 Version Permalink: http://hdl.handle.net/21.11116/0000-0003-D0BE-C
Genre: Journal Article

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e201800070.full.pdf (Publisher version), 3MB
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© 2018 Hartmann et al.

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https://doi.org/10.26508/lsa.201800054 (Supplementary material)
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 Creators:
Hartmann, Hannelore1, Author
Hornburg, Daniel2, Author              
Czuppa, Mareike1, Author
Bader, Jakob2, Author              
Michaelsen, Meike1, Author
Farny, Daniel1, Author
Arzberger, Thomas1, Author
Mann, Matthias2, Author              
Meissner, Felix3, Author              
Edbauer, Dieter1, Author
Affiliations:
1external, ou_persistent22              
2Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              
3Meissner, Felix / Experimental Systems Immunology, Max Planck Institute of Biochemistry, Max Planck Society, ou_2149678              

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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 ribosomes may chronically impair protein synthesis even in the absence of nucleolar localization and contribute to pathogenesis.

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 Dates: 2018-05
 Publication Status: Published online
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 Identifiers: ISI: 000457325800008
DOI: 10.26508/lsa.201800070
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Project name : ToPAG
Grant ID : 318987
Funding program : European Community’s Health Seventh Framework Programme
Funding organization : European Commission (EC)
Project name : EUROMOTOR
Grant ID : 259867
Funding program : European Community’s Health Seventh Framework Programme
Funding organization : European Commission (EC)

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Title: Life Science Alliance
Source Genre: Journal
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Pages: - Volume / Issue: 1 (2) Sequence Number: e201800070 Start / End Page: - Identifier: ISSN: 2575-1077