Global proteomics of Ubqln 2-based murine models of ALS
Global proteomics of Ubqln 2-based murine models of ALS
Abstract Familial forms of neurodegenerative diseases commonly involve mutation of aggregation-prone proteins or components of the protein degradation machinery that act on aberrant proteins. Ubqln2 encodes a member of the UBL/UBA family of proteasome shuttle factors that is thought to facilitate proteasomal degradation of substrates, and mutation of this gene results in a familial form of ALS/FTD in humans. How Ubqln2 dysfunction leads to neurodegeneration, however, remains uncertain. We undertook a comprehensive study to identify proteomic changes upon Ubqln2 perturbation in multiple murine models of Ubqln2-mediated neurodegenerative disease. By performing quantitative multiplexed proteomics on neural tissues of affected animals, we identified a small group of proteins whose abundance is tightly linked to UBQLN2 function: the ubiquitin ligase TRIM32 and two retroelement-derived proteins, PEG10 and CXX1B. Further studies using cultured cells of human origin, including induced neurons, found similar changes in protein abundance upon Ubqln2 loss, and pulse-chase studies suggested that PEG10 and TRIM32 are direct clients of UBQLN2. In conclusion, our study provides a deep understanding of 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.
Whiteley Alexandra M.、Prado Miguel A.、Paulo Joao A.、Ashton Marissa、Weber Martin、Monteiro Mervyn J.、Kurz Thimo、Szpyt John、Finley Daniel、Gygi Steven P.、Brown Eric J.、Dominguez Sara、Jedrychowski Mark P.、de Poot Stefanie A.H.、Ngu Hai、Easton Amy
Department of Cell Biology, Harvard Medical School||Department of Biochemistry, University of Colorado BoulderDepartment of Cell Biology, Harvard Medical SchoolDepartment of Cell Biology, Harvard Medical SchoolDepartment of Cell Biology, Harvard Medical SchoolDepartment of Neuroscience, Genentech Inc.Center for Biomedical Engineering and Technology, Department of Anatomy and Neurobiology, University of Maryland Medical SchoolHenry Wellcome Lab of Cell Biology, College of Medical, Veterinary and Life Sciences, Institute of Molecular, Cell and Systems Biology, University of Glasgow, University AvenueDepartment of Cell Biology, Harvard Medical SchoolDepartment of Cell Biology, Harvard Medical SchoolDepartment of Cell Biology, Harvard Medical SchoolDepartment of Immunology and Infectious DiseasesDepartment of Neuroscience, Genentech Inc.Department of Cell Biology, Harvard Medical SchoolDepartment of Cell Biology, Harvard Medical SchoolDepartment of Pathology, Genentech Inc.Department of Neuroscience, Genentech Inc.
神经病学、精神病学基础医学分子生物学
Whiteley Alexandra M.,Prado Miguel A.,Paulo Joao A.,Ashton Marissa,Weber Martin,Monteiro Mervyn J.,Kurz Thimo,Szpyt John,Finley Daniel,Gygi Steven P.,Brown Eric J.,Dominguez Sara,Jedrychowski Mark P.,de Poot Stefanie A.H.,Ngu Hai,Easton Amy.Global proteomics of Ubqln 2-based murine models of ALS[EB/OL].(2025-03-28)[2025-05-02].https://www.biorxiv.org/content/10.1101/2020.02.22.956524.点此复制
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