Proteomic Analysis of Huntington’s Disease Medium Spiny Neurons Identifies Alterations in Lipid Droplets
Rattachement africain : us, cl. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
Huntington's disease (HD) is a neurodegenerative disease caused by a CAG repeat expansion in the Huntingtin (HTT) gene. The resulting polyglutamine (polyQ) tract alters the function of the HTT protein. Although HTT is expressed in different tissues, the medium-spiny projection neurons (MSNs) in the striatum are particularly vulnerable in HD. Thus, we sought to define the proteome of human HD patient-derived MSNs. We differentiated HD72-induced pluripotent stem cells and isogenic controls into MSNs and carried out quantitative proteomic analysis. Using data-dependent acquisitions with FAIMS for label-free quantification on the Orbitrap Lumos mass spectrometer, we identified 6323 proteins with at least two unique peptides. Of these, 901 proteins were altered significantly more in the HD72-MSNs than in isogenic controls. Functional enrichment analysis of upregulated proteins demonstrated extracellular matrix and DNA signaling (DNA replication pathway, double-strand break repair, G1/S transition) with the highest significance. Conversely, processes associated with the downregulated proteins included neurogenesis-axogenesis, the brain-derived neurotrophic factor-signaling pathway, Ephrin-A:EphA pathway, regulation of synaptic plasticity, triglyceride homeostasis cholesterol, plasmid lipoprotein particle immune response, interferon-γ signaling, immune system major histocompatibility complex, lipid metabolism, and cellular response to stimulus. Moreover, proteins involved in the formation and maintenance of axons, dendrites, and synapses (e.g., septin protein members) were dysregulated in HD72-MSNs. Importantly, lipid metabolism pathways were altered, and using quantitative image analysis, we found that lipid droplets accumulated in the HD72-MSN, suggesting a deficit in the turnover of lipids possibly through lipophagy. Our proteomics analysis of HD72-MSNs identified relevant pathways that are altered in MSNs and confirm current and new therapeutic targets for HD.
Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.
Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Proteomic Analysis of Huntington’s Disease Medium Spiny Neurons Identifies Alterations in Lipid Droplets
- Date Crossref
- 01/05/2023
- Éditeur
- Elsevier BV
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
-
Buck Institute for Research on Aging pays non établi dans la noticeOrganisation à but non lucratif
-
University of Southern California pays non établi dans la noticeUniversité ou école supérieure
-
National Institute on Aging Translational Gerontology Branch pays non établi dans la noticeStructure de recherche
-
University of Washington Medical Center pays non établi dans la noticeÉtablissement de santé
-
Center for Climate and Resilience Research pays non établi dans la noticeStructure de recherche
-
University of Chile Institute of Biomedical Sciences pays non établi dans la noticeUniversité ou école supérieure
-
Leonard Davis School of Gerontology The Buck Institute for Research on Aging pays non établi dans la noticeUniversité ou école supérieure
-
School of Medicine Department of Biomedical Informatics and Medical Education pays non établi dans la noticeUniversité ou école supérieure
-
Faculty of Medicine The Buck Institute for Research on Aging pays non établi dans la noticeUniversité ou école supérieure
-
Center for Geroscience pays non établi dans la noticeInstitution
Buck Institute for Research on Aging, University of Southern California et Translational Gerontology Branch — National Institute on Aging, avec 7 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.