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Hum Mol Genet. 2014 Jan 1;23(1):104-16. doi: 10.1093/hmg/ddt402. Epub 2013 Aug 19.

Acetylation of the KXGS motifs in tau is a critical determinant in modulation of tau aggregation and clearance.

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  • 1Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.

Abstract

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.

PMID:
23962722
[PubMed - indexed for MEDLINE]
PMCID:
PMC3857946
Free PMC Article

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