Proteomics

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Quantitative PTM Maps of Human Pathologic Tau Identify Patient Heterogeneity and Define Critical Steps in Alzheimer’s Disease Progression - frontal gyrus (sarkosyl soluble)

ABSTRACT: To elucidate the role of Tau isoforms and PTM stoichiometry in Alzheimer’s disease (AD), we generated a high resolution quantitative proteomic map of 88 PTMs on multiple isoforms of Tau isolated from the post-mortem human tissue from 49 AD and 42 control subjects. While Tau PTM maps reveal heterogeneity across subjects, a subset of PTMs display high occupancy and patient frequency for AD suggesting importance in disease. Unsupervised analyses indicate that PTMs occur in an ordered manner leading to Tau aggregation. The processive addition and minimal set of PTMs associated with seeding activity was further defined by the analysis of size fractionated Tau. To summarize, critical features within the Tau protein for disease intervention at different stages of disease are identified, including enrichment of 0N and 4R isoforms, underrepresentation of the C-terminal, an increase in negative charge in the PRR and a decrease in positive charge in the MBD.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Judith A. Steen  

PROVIDER: MSV000088409 | MassIVE | Thu Nov 18 09:53:00 GMT 2021

SECONDARY ACCESSION(S): PXD020717

REPOSITORIES: MassIVE

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To elucidate the role of Tau isoforms and post-translational modification (PTM) stoichiometry in Alzheimer's disease (AD), we generated a high-resolution quantitative proteomics map of 95 PTMs on multiple isoforms of Tau isolated from postmortem human tissue from 49 AD and 42 control subjects. Although Tau PTM maps reveal heterogeneity across subjects, a subset of PTMs display high occupancy and frequency for AD, suggesting importance in disease. Unsupervised analyses indicate that PTMs occur in  ...[more]

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