A dual pathogenic mechanism links tau acetylation to sporadic tauopathy

Hanna Trzeciakiewicz, Jui Heng Tseng, Connor M. Wander, Victoria Madden, Ashutosh Tripathy, Chao Xing Yuan, Todd J. Cohen

Research output: Research - peer-reviewArticle

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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.

LanguageEnglish (US)
Article number44102
JournalScientific Reports
Volume7
DOIs
StatePublished - Mar 13 2017

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Tauopathies
Acetylation
Microtubules
Alzheimer Disease
Pathology
Methylene Blue
Post Translational Protein Processing
Mass Spectrometry
Seeds
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

Trzeciakiewicz, H., Tseng, J. H., Wander, C. M., Madden, V., Tripathy, A., Yuan, C. X., & Cohen, T. J. (2017). A dual pathogenic mechanism links tau acetylation to sporadic tauopathy. Scientific Reports, 7, [44102]. DOI: 10.1038/srep44102

A dual pathogenic mechanism links tau acetylation to sporadic tauopathy. / Trzeciakiewicz, Hanna; Tseng, Jui Heng; Wander, Connor M.; Madden, Victoria; Tripathy, Ashutosh; Yuan, Chao Xing; Cohen, Todd J.

In: Scientific Reports, Vol. 7, 44102, 13.03.2017.

Research output: Research - peer-reviewArticle

Trzeciakiewicz, H, Tseng, JH, Wander, CM, Madden, V, Tripathy, A, Yuan, CX & Cohen, TJ 2017, 'A dual pathogenic mechanism links tau acetylation to sporadic tauopathy' Scientific Reports, vol 7, 44102. DOI: 10.1038/srep44102
Trzeciakiewicz H, Tseng JH, Wander CM, Madden V, Tripathy A, Yuan CX et al. A dual pathogenic mechanism links tau acetylation to sporadic tauopathy. Scientific Reports. 2017 Mar 13;7. 44102. Available from, DOI: 10.1038/srep44102
Trzeciakiewicz, Hanna ; Tseng, Jui Heng ; Wander, Connor M. ; Madden, Victoria ; Tripathy, Ashutosh ; Yuan, Chao Xing ; Cohen, Todd J./ A dual pathogenic mechanism links tau acetylation to sporadic tauopathy. In: Scientific Reports. 2017 ; Vol. 7.
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