Quantitative Analysis of the Brain Ubiquitylome in Alzheimer's Disease
In: Proteomics, Jg. 18 (2018-03-12), Heft 20
Online
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Zugriff:
Several neurodegenerative diseases including Alzheim er’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 identified 4,291 unique ubiquitylation sites mapping to 1,682 unique proteins. Differential enrichment analysis showed that over 800 ubiquitylation sites were significantly altered between AD and control cases. Of these, approximately 80% were increased in AD, including seven polyubiquitin 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, had the highest number of increased sites of ubiquitylation per any protein in AD. Tau polyubiquitylation from AD brain homogenates was confirmed by reciprocal co-immunoprecipitation and by affinity capture using tandem ubiquitin binding entities (TUBEs). Co-modified peptides, with both ubiquitylation and phosphorylation sites, were also enriched in AD. Notably, many of the co-modified peptides mapped to Tau within KXGS motifs in the microtubule binding repeat suggesting that cross-talk 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.
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Quantitative Analysis of the Brain Ubiquitylome in Alzheimer's Disease
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Autor/in / Beteiligte Person: | Abreha, Measho ; Ping, Lingyan ; Dammer, Eric B. ; Seyfried, Nicholas T. ; Lah, James J. ; Zhang, Tian ; Duong, Duc M. ; Levey, Allan I. ; Gearing, Marla |
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Zeitschrift: | Proteomics, Jg. 18 (2018-03-12), Heft 20 |
Veröffentlichung: | 2018 |
Medientyp: | unknown |
ISSN: | 1615-9861 (print) |
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