PXD008691

PXD008691 is an original dataset announced via ProteomeXchange.

Title	Translation deficits drive C9orf72 associated poly-GR/PR toxicity
Description	Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) patients with the C9orf72 mutation show predominantly cytoplasmic aggregates of poly-GR and poly-PR proteins that are acutely toxic in various model systems. To identify the molecular mediators of neurotoxicity of poly-GR/PR, we analyzed their interactomes in primary neurons. GFP-(GR)149 and (PR)175-GFP preferentially interacted with RNA-binding proteins, including stress granule-associated and nucleolar proteins, as well as ribosomes. Overexpression of the poly-GR/PR interactors Staufen 1/2 (STAU1/2) and YBX1 led to cytoplasmic aggregation of poly-GR/PR into large stress granule-like inclusions, while the poly-GR/PR interactor nucleophosmin (NPM1) recruited poly-GR into the nucleolus. In addition, poly-PR expression reduced ribosome levels and translation, which is consistent with the widespread reduction of synaptic proteins detected by proteomics. Surprisingly, only GFP-(GR)53, but not GFP-(GR)149, localized to the nucleolus and reduced ribosome levels and translation in neurons, suggesting impaired ribosome biogenesis is driving the acute toxicity commonly observed in vitro. In C9orf72 patient brains, we detected co-aggregation of poly-GR/PR inclusions with ribosomes, but not stress granules. Partial sequestration of ribosomes may chronically impair protein synthesis and contribute to C9orf72 ALS/FTD pathogenesis.
HostingRepository	PRIDE
AnnounceDate	2018-06-27
AnnouncementXML	Submission_2018-06-27_04:20:59.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mario Oroshi
SpeciesList	scientific name: Rattus norvegicus (Rat); NCBI TaxID: 10116; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2018-01-16 07:48:59	ID requested
⏵ 1	2018-06-27 04:21:00	announced

Dataset with its publication pending

curator keyword: Biomedical

submitter keyword: C9orf72, ALS, FTLD, interactome, DPR proteins, ribosome, nucleolus, translation, stress granules, proteomics

Dieter Edbauer
contact affiliation	DZNE: German center for Neurodegenerative Diseases, Munich, https://www.dzne.de/index.php?id=105&L=1
contact email	dieter.edbauer@dzne.de
lab head
Mario Oroshi
contact affiliation	Proteomics
contact email	oroshi@biochem.mpg.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD008691
     1. Label: PRIDE project
     2. Name: Translation deficits drive C9orf72 associated poly-GR/PR toxicity