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• W2891480565 endingPage "1800108" @default.
• W2891480565 startingPage "1800108" @default.
• W2891480565 abstract "Several neurodegenerative diseases including Alzheimer's Disease (AD) are characterized by ubiquitin-positive pathological protein aggregates. Here, an immunoaffinity approach is utilized to enrich ubiquitylated isopeptides after trypsin digestion from five AD and five age-matched control postmortem brain tissues. Label-free MS-based proteomic analysis identifies 4291 unique ubiquitylation sites mapping to 1682 unique proteins. Differential enrichment analysis shows that over 800 ubiquitylation sites are significantly altered between AD and control cases. Of these, ≈80% are increased in AD, including seven poly ubiquitin linkages, which is consistent with proteolytic stress and high burden of ubiquitylated pathological aggregates in AD. The microtubule associated protein Tau, the core component of neurofibrillary tangles, has the highest number of increased sites of ubiquitylation per any protein in AD. Tau poly ubiquitylation from AD brain homogenates is confirmed by reciprocal co-immunoprecipitation and by affinity capture using tandem ubiquitin binding entities. Co-modified peptides, with both ubiquitylation and phosphorylation sites, are also enriched in AD. Notably, many of the co-modified peptides mapped to Tau within KXGS motifs in the microtubule binding region suggesting that crosstalk between phosphorylation and ubiquitylation occurs on Tau in AD. Overall, these findings highlight the utility of MS to map ubiquitylated substrates in human brain and provides insight into mechanisms underlying pathological protein posttranslational modification in AD." @default.
• W2891480565 created "2018-09-27" @default.
• W2891480565 creator A5022349887 @default.
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• W2891480565 date "2018-10-01" @default.
• W2891480565 modified "2023-10-17" @default.
• W2891480565 title "Quantitative Analysis of the Brain Ubiquitylome in Alzheimer's Disease" @default.
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• W2891480565 doi "https://doi.org/10.1002/pmic.201800108" @default.
• W2891480565 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6283072" @default.
• W2891480565 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/30230243" @default.
• W2891480565 hasPublicationYear "2018" @default.
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