title: A Dual Pathogenic Mechanism Links Tau Acetylation to Sporadic Tauopathy.
abstract: Tau acetylation has recently emerged as a dominant post-translational modification (PTM) in Alzheimer's disease (AD) and related tauopathies. Mass spectrometry studies indicate that tau acetylation sites cluster within the microtubule (MT)-binding region (MTBR), suggesting acetylation could regulate both normal and pathological tau functions. Here, we combined biochemical and cell-based approaches to uncover a dual pathogenic mechanism mediated by tau acetylation. We show that acetylation specifically at residues K280/K281 impairs tau-mediated MT stabilization, and enhances the formation of fibrillar tau aggregates, highlighting both loss and gain of tau function. Full-length acetylation-mimic tau showed increased propensity to undergo seed-dependent aggregation, revealing a potential role for tau acetylation in the propagation of tau pathology. We also demonstrate that methylene blue, a reported tau aggregation inhibitor, modulates tau acetylation, a novel mechanism of action for this class of compounds. Our study identifies a potential "two-hit" mechanism in which tau acetylation disengages tau from MTs and also promotes tau aggregation. Thus, therapeutic approaches to limit tau K280/K281 acetylation could simultaneously restore MT stability and ameliorate tau pathology in AD and related tauopathies.
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Hanna
authors.initials: H
authors.lastname: Trzeciakiewicz
authors.affiliation: Department of Neurology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Jui-Heng
authors.initials: JH
authors.lastname: Tseng
authors.affiliation: Department of Neurology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Connor M
authors.initials: CM
authors.lastname: Wander
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Madden
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Tripathy
authors.affiliation: Alexion Pharmaceuticals Inc, New Haven, Connecticut 06510, USA.
authors.forename: Chao-Xing
authors.initials: CX
authors.lastname: Yuan
authors.affiliation: Department of Neurology, UNC Neuroscience Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Cohen
mesh_terms: D000107:Acetylation; D000818:Animals; D002460:Cell Line; D006801:Humans; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D010766:Phosphorylation; D066263:Protein Aggregation, Pathological / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D024801:Tauopathies / Q000378:metabolism* / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins