PXD024120-1

PXD024120 is an original dataset announced via ProteomeXchange.

Title	Interactome screening of C9orf72 dipeptide repeats reveals sequestration and functional impairment of VCP by polyGA
Description	Repeat expansions in the C9orf72 gene are a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), two devastating neurodegenerative disorders. One of the proposed mechanisms of GGGGCC repeat expansion is their translation to produce unnatural dipeptide repeat (DPR) proteins that accumulate in aggregates and contribute to the pathology. There are 5 different DPRs poly(GA), poly(GR), poly(PR), poly(PA), poly(GP) which are neurotoxic in vitro. In our study, we identified the interactome of all five DPR proteins, consisting of 125 repeats, overexpressed in HEK293T cells using BioID2 proximity labeling. We identified 140 interacting partners for polyGR, 130 for polyGA, 138 for polyPR, 62 for polyPA, and 38 for polyGP. Gene ontology enrichment analysis of proteomic data identified interaction candidates involved in protein translation, signal transduction pathways, protein catabolic processes, amide metabolic processes, and RNA-binding. Through further analyses, we evaluated the interaction between polyGA and Valosin-containing protein (VCP) in HEK293T cells as well as in brains of C9orf72 patients. Furthermore, we are showing that polyGA sequester VCP in polyGA aggregates and hinders its function. Additionally, we analyzed the effect of decreased level of VCP on autophagic markers p62 and LC3.
HostingRepository	PRIDE
AnnounceDate	2022-05-19
AnnouncementXML	Submission_2022-05-19_15:26:06.231.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Andrew Thompson
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2021-02-10 23:49:22	ID requested
⏵ 1	2022-05-19 15:26:07	announced

Bo, ž, i, č J, Motaln H, Jane, ž AP, Marki, č L, Tripathi P, Yamoah A, Aronica E, Lee YB, Heilig R, Fischer R, Thompson AJ, Goswami A, Rogelj B, Interactome screening of C9orf72 dipeptide repeats reveals VCP sequestration and functional impairment by polyGA. Brain, 145(2):684-699(2022) [pubmed]

submitter keyword: dipeptide repeats, proteomics, proximity labeeling, BioID, neurodegeneration, amyotrophic lateral sclerosis, ALS, Valosin-containing protein, VCP

Boris Rogelj
contact affiliation	Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia
contact email	boris.rogelj@ijs.si
lab head
Andrew Thompson
contact affiliation	InViva Consulting Ltd
contact email	a.thompson@invivaconsulting.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD024120
     1. Label: PRIDE project
     2. Name: Interactome screening of C9orf72 dipeptide repeats reveals sequestration and functional impairment of VCP by polyGA