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

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.

Tau-induced neurodegeneration: mechanisms and targets

“…However, another study showed that the expression of histone deacetylase 6 (HDAC6) positively correlates with tau burden, while a decrease in HDAC6 activity or expression promotes tau clearance [67] , and its levels have also been shown to be elevated in the brains of patients with AD and transgenic mice [68,69] . Thus, a better understanding of the relationship of these acetylation residues with phosphorylation could be crucial to identify potential targets for therapy in AD and other tauopathies.…”

“…Using antibodies specific for acetylated tau, it has been shown that tau acetylation is elevated in patients at early and moderate Braak stages of tauopathy [66] . Meanwhile, they demonstrated that deacetylase SIRT1 deficiency leads to hyperacetylation of tau and accumulation of p-tau, while in contrast, promoting tau deacetylation eliminates p-tau.However, another study showed that the expression of histone deacetylase 6 (HDAC6) positively correlates Cindy Beharry, et al Tau-induced neurodegeneration: mechanisms and targets 349 with tau burden, while a decrease in HDAC6 activity or expression promotes tau clearance [67] , and its levels have also been shown to be elevated in the brains of patients with AD and transgenic mice [68,69] . Thus, a better understanding of the relationship of these acetylation residues with phosphorylation could be crucial to identify potential targets for therapy in AD and other tauopathies.…”

Protein aggregate formation in oligodendrocytes: tau and the cytoskeleton at the intersection of neuroprotection and neurodegeneration

“…Acetylation of tau in neurons is mediated by p300 acetyltransferase and CREB-binding protein (CBP) possibly at different sites Brought to you by | MIT Libraries Authenticated Download Date | 5/12/18 1:47 PM (Cohen et al, 2011;Cook et al, 2014). Experiments carried out by Min et al (2010) suggested that the deacetylase sirtuin 1 (SIRT1), which is localized exclusively in neurons, may be involved in tau deacetylation.…”

Structure-based virtual screening campaigns on curcuminoids as potent ligands for histone deacetylase-2

“…As HDAC inhibitors, these curcuminoids may alter phosphorylation 30 and/ or reduce the stability of tau protein 31,32 , resulting in decreased clinical features of tauopathies, a class of neurodegenerative diseases associated with the pathological aggregation of tau protein in the human brain. The best known of these illnesses is Alzheimer's disease, wherein tau protein is deposited within neurons in the form of neurofibrillary tangles.These curcuminoids as HDAC inhibitors couldal so suppress cancer by inducing the G1/S phase arrest primarily through transcriptional changes in cell cycle regulatory genes 33 .…”