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dc.contributor.authorWhiteley, Alexandra M
dc.contributor.authorPrado, Miguel A
dc.contributor.authorde Poot, Stefanie A H
dc.contributor.authorPaulo, Joao A
dc.contributor.authorAshton, Marissa
dc.contributor.authorDominguez, Sara
dc.contributor.authorWeber, Martin
dc.contributor.authorNgu, Hai
dc.contributor.authorSzpyt, John
dc.contributor.authorJedrychowski, Mark P
dc.contributor.authorEaston, Amy
dc.contributor.authorGygi, Steven P
dc.contributor.authorKurz, Thimo
dc.contributor.authorMonteiro, Mervyn J
dc.contributor.authorBrown, Eric J
dc.contributor.authorFinley, Daniel
dc.date.accessioned2021-03-29T18:46:41Z
dc.date.available2021-03-29T18:46:41Z
dc.date.issued2020-12-04
dc.identifier.urihttp://hdl.handle.net/10713/15054
dc.description.abstractFamilial 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.en_US
dc.description.urihttps://doi.org/10.1074/jbc.RA120.015960en_US
dc.language.isoenen_US
dc.publisherAmerican Society for Biochemistry and Molecular Biology Inc.en_US
dc.relation.ispartofJournal of Biological Chemistryen_US
dc.rightsPublished under license by The American Society for Biochemistry and Molecular Biology, Inc.en_US
dc.subjectE3 ubiquitin ligaseen_US
dc.subjectUBQLN2en_US
dc.subjectamyotrophic lateral sclerosis (ALS) (Lou Gehrig disease)en_US
dc.subjectneurodegenerationen_US
dc.subjectproteasomeen_US
dc.subjectproteomicsen_US
dc.subjectubiquitinen_US
dc.titleGlobal proteomics of Ubqln2-based murine models of ALSen_US
dc.typeArticleen_US
dc.identifier.doi10.1074/jbc.RA120.015960
dc.identifier.pmid33277362
dc.source.countryUnited States


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