| Literature DB >> 33188775 |
Hendrik Wesseling1, Waltraud Mair1, Mukesh Kumar1, Christoph N Schlaffner1, Shaojun Tang2, Pieter Beerepoot1, Benoit Fatou3, Amanda J Guise1, Long Cheng1, Shuko Takeda4, Jan Muntel3, Melissa S Rotunno3, Simon Dujardin5, Peter Davies6, Kenneth S Kosik7, Bruce L Miller8, Sabina Berretta9, John C Hedreen9, Lea T Grinberg10, William W Seeley10, Bradley T Hyman5, Hanno Steen3, Judith A Steen11.
Abstract
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 an ordered manner, leading to Tau aggregation. The processive addition and minimal set of PTMs associated with seeding activity was further defined by analysis of size-fractionated Tau. To summarize, features in the Tau protein critical for disease intervention at different stages of disease are identified, including enrichment of 0N and 4R isoforms, underrepresentation of the C terminus, an increase in negative charge in the proline-rich region (PRR), and a decrease in positive charge in the microtubule binding domain (MBD).Entities:
Keywords: FLEXITau; absolute quantification; disease progression; multiple reaction monitoring (MRM); post-translational modifications; prion-like molecules; protein aggregation; proteomics; proteopathy; quantitative mass spectrometry
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Year: 2020 PMID： 33188775 DOI： 10.1016/j.cell.2020.10.029
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582