title: FLEXITau: Quantifying Post-translational Modifications of Tau Protein in Vitro and in Human Disease.
abstract: Tauopathies, including Alzheimer's disease (AD), are associated with the aggregation of modified microtubule associated protein tau. This pathological state of tau is often referred to as "hyperphosphorylated". Due to limitations in technology, an accurate quantitative description of this state is lacking. Here, a mass spectrometry-based assay, FLEXITau, is presented to measure phosphorylation stoichiometry and provide an unbiased quantitative view of the tau post-translational modification (PTM) landscape. The power of this assay is demonstrated by measuring the state of hyperphosphorylation from tau in a cellular model for AD pathology, mapping, and calculating site occupancies for over 20 phosphorylations. We further employ FLEXITau to define the tau PTM landscape present in AD post-mortem brain. As shown in this study, the application of this assay provides mechanistic understanding of tau pathology that could lead to novel therapeutics, and we envision its further use in prognostic and diagnostic approaches for tauopathies.
authors.affiliation: F. M. Kirby Neurobiology Center, Boston Children's Hospital , Boston, Massachusetts 02115, United States.|Department of Neurology, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Waltraud
authors.initials: W
authors.lastname: Mair
authors.affiliation: Pathology, Boston Children's Hospital , Boston, Massachusetts 02115, United States.|Pathology, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Jan
authors.initials: J
authors.lastname: Muntel
authors.affiliation: DZNE, German Center for Neurodegenerative Diseases , 53175 Bonn, Germany.|CAESAR, Center of Advanced European Studies and Research , 53175 Bonn, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Tepper
authors.affiliation: Pathology, Boston Children's Hospital , Boston, Massachusetts 02115, United States.|Pathology, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Shaojun
authors.initials: S
authors.lastname: Tang
authors.affiliation: DZNE, German Center for Neurodegenerative Diseases , 53175 Bonn, Germany.|CAESAR, Center of Advanced European Studies and Research , 53175 Bonn, Germany.
authors.forename: Jacek
authors.initials: J
authors.lastname: Biernat
authors.affiliation: Memory and Aging Center, Department of Neurology, University of California , San Francisco, California 94158, United States.|Department of Pathology, University of California , San Francisco, California 94143, United States.
authors.forename: William W
authors.initials: WW
authors.lastname: Seeley
authors.affiliation: Neuroscience Research Institute, University of California Santa Barbara , Santa Barbara, California 93106, United States.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Kosik
authors.affiliation: DZNE, German Center for Neurodegenerative Diseases , 53175 Bonn, Germany.|CAESAR, Center of Advanced European Studies and Research , 53175 Bonn, Germany.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Mandelkow
authors.affiliation: Pathology, Boston Children's Hospital , Boston, Massachusetts 02115, United States.|Pathology, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Hanno
authors.initials: H
authors.lastname: Steen
authors.affiliation: F. M. Kirby Neurobiology Center, Boston Children's Hospital , Boston, Massachusetts 02115, United States.|Department of Neurology, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Steen
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D006801:Humans; D013058:Mass Spectrometry; D010750:Phosphoproteins / Q000032:analysis* / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D061987:Sf9 Cells; D018411:Spodoptera; D016875:tau Proteins / Q000032:analysis* / Q000378:metabolism
chemical_list: D010750:Phosphoproteins; D016875:tau Proteins