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.
[doi:10.25345/C50S1T]
[dataset license: CC0 1.0 Universal (CC0 1.0)]
Keywords: Alzheimer's disease ; post-translational modification ; clinical progression ; srm ; lfq ; human tau ; protein aggregation ; proteopathy
Principal Investigators: (in alphabetical order) |
Judith A. Steen, Department of Neurobiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA, N/A |
Submitting User: | ccms |
Wesseling H, Mair W, Kumar M, Schlaffner CN, Tang S, Beerepoot P, Fatou B, Guise AJ, Cheng L, Takeda S, Muntel J, Rotunno MS, Dujardin S, Davies P, Kosik KS, Miller BL, Berretta S, Hedreen JC, Grinberg LT, Seeley WW, Hyman BT, Steen H, Steen JA.
Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer's Disease.
Cell. 2020 Dec 10;183(6):1699-1713.e13. Epub 2020 Nov 13.
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