Proteomics

Dataset Information

0

Mapping Ubiquitination Sites in Alzheimer's Disease


ABSTRACT: Alzheimer’s Disease (AD) is characterized by the deposition of protein aggregates such as neurofibrillary tangles (NFTs) and amyloid (Aβ) plaques in the brain. Post-translational modification through ubiquitylationplays critical roles in clearing misfolded protein aggregates. Investigating global ubiquitylation changes inAD brain may provide insights regarding the underlying mechanisms of proteostasis and disease pathogenesis.Here, we utilizedan immunoaffinity approach to specifically enrichubiquitinated(di-glycine) peptides frompostmortemhuman control and AD braintissues.Mass spectrometry(MS)based proteomicanalysis identified global ubiquitylation changes associated with ADand hierarchical clustering of the human brain ubiquitylome clearly classified AD cases from healthy controls based on ubiquitylation patterns. Polyubiquitin linkage analysis identified increased levels of all seven polyubiquitin linkage typesas well as total ubiquitin in the AD brain tissues.We also report novel ubiquitylation sites in the microtubulebinding repeatof Tauwith potential implicationsfor Tauaggregation. Dually modified peptides with both phosphorylation and ubiquitylationsites, many of which originated from Tauprotein are also differentially enriched in AD.Furthermore, all the KXGS motifswithin themicrotubule binding region (MTBR)of Tauprotein,which represents the core ofNFTs,are enriched among dually modified peptides. Collectively, these studieshighlight the utility of an immunoaffinity enrichment approach coupled with MSanalysis for mapping AD associated global ubiquitylome changesas well as to gain insights intounderlying proteostasis pathwaysaltered in AD brain.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Alzheimer's Disease

SUBMITTER: Eric Dammer  

LAB HEAD: Nicholas T. Seyfried

PROVIDER: PXD009199 | Pride | 2019-06-25

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
AD1.raw Raw
AD2.raw Raw
AD5.raw Raw
AD6.raw Raw
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Publications

Quantitative Analysis of the Brain Ubiquitylome in Alzheimer's Disease.

Abreha Measho H MH   Dammer Eric B EB   Ping Lingyan L   Zhang Tian T   Duong Duc M DM   Gearing Marla M   Lah James J JJ   Levey Allan I AI   Seyfried Nicholas T NT  

Proteomics 20181001 20


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  ...[more]

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