PXD021991

PXD021991 is an original dataset announced via ProteomeXchange.

Title	Global proteomics of Ubqln2-based murine models of ALS
Description	Familial neurodegenerative diseases commonly involve mutations that result in either aberrant proteins or dysfunctional components of the proteolytic machinery that acts on aberrant proteins. UBQLN2 is a ubiquitin receptor of the UBL/UBA family that binds the proteasome through its ubiquitin-like (UBL) domain and is thought to deliver ubiquitinated proteins to proteasomes for degradation. UBQLN2 mutations result in familial ALS/FTD in humans through an unknown mechanism. Quantitative multiplexed proteomics was used to provide for the first time an unbiased and global analysis of the role of Ubqln2 in controlling the composition of the proteome. We studied several murine models of Ubqln2-linked ALS and also generated Ubqln2 null mutant mice. We identified impacts of Ubqln2 on diverse physiological pathways, most notably serotonergic signaling. Interestingly, we observed upregulation of proteasome subunits, suggesting a compensatory response to diminished proteasome output. Among the specific proteins whose abundance is linked to UBQLN2 function, the strongest hits were the ubiquitin ligase TRIM32 and two retroelement-derived proteins, PEG10 and CXX1B. Cycloheximide chase studies using induced human neurons and HEK293 cells suggested that PEG10 and TRIM32 are direct clients. Although directing the degradation of multiple proteins via the proteasome, UBQLN2 surprisingly conferred strong protection from degradation on the Gag-like protein CXX1B, which is expressed from the same family of retroelement genes as PEG10. In summary, this study charts the proteomic landscape of ALS-related Ubqln2 mutants and identifies candidate client proteins that are altered in vivo in disease models and whose degradation is promoted by UBQLN2.
HostingRepository	PRIDE
AnnounceDate	2021-01-20
AnnouncementXML	Submission_2021-01-19_22:05:55.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD021991
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Miguel Prado
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos; Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2020-10-15 00:13:23	ID requested
⏵ 1	2021-01-19 22:05:56	announced

Whiteley AM, Prado MA, de Poot SAH, Paulo JA, Ashton M, Dominguez S, Weber M, Ngu H, Szpyt J, Jedrychowski MP, Easton A, Gygi SP, Kurz T, Monteiro MJ, Brown EJ, Finley D, Global proteomics of Ubqln2-based murine models of ALS. J Biol Chem, 296():100153(2021) [pubmed]

submitter keyword: ubiquitin, proteasome, ALS, neurodegeneration, proteomics, ubiquitin ligase, UBQLN2

Daniel Finley
contact affiliation	Finley and Gygi lab Cell Biology Department Harvard Medical School US
contact email	daniel_finley@hms.harvard.edu
lab head
Miguel Prado
contact affiliation	Harvard Medical School
contact email	miguel_prado@hms.harvard.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD021991
     1. Label: PRIDE project
     2. Name: Global proteomics of Ubqln2-based murine models of ALS