Journal
HUMAN MOLECULAR GENETICS
Volume 23, Issue 1, Pages 104-116Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddt402
Keywords
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Funding
- Mayo Clinic Foundation
- National Institutes of Health/National Institute on Aging [5R01AG026251-04, AG17216-10JP3]
- National Institutes of Health/National Institute of Neurological Disorders and Stroke [R01 NS 063964-01, U01NS065102-1, R01 NS077402]
- BrightFocus Foundation [A2013546S]
- Acetylon Pharmaceuticals Inc.
- ADRC [AG016574]
- Mayo Clinic
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The accumulation of hyperphosphorylated tau in neurofibrillary tangles (NFTs) is a neuropathological hallmark of tauopathies, including Alzheimer's disease (AD) and chronic traumatic encephalopathy, but effective therapies directly targeting the tau protein are currently lacking. Herein, we describe a novel mechanism in which the acetylation of tau on KXGS motifs inhibits phosphorylation on this same motif, and also prevents tau aggregation. Using a site-specific antibody to detect acetylation of KXGS motifs, we demonstrate that these sites are hypoacetylated in patients with AD, as well as a mouse model of tauopathy, suggesting that loss of acetylation on KXGS motifs renders tau vulnerable to pathogenic insults. Furthermore, we identify histone deacetylase 6 (HDAC6) as the enzyme responsible for the deacetylation of these residues, and provide proof of concept that acute treatment with a selective and blood-brain barrier-permeable HDAC6 inhibitor enhances acetylation and decreases phosphorylation on tau's KXGS motifs in vivo. As such, we have uncovered a novel therapeutic pathway that can be manipulated to block the formation of pathogenic tau species in disease.
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