title: 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.
authors: Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
authors: Casey
authors: C
authors: Cook
authors: Yari
authors: Y
authors: Carlomagno
authors: Tania F
authors: TF
authors: Gendron
authors: Judy
authors: J
authors: Dunmore
authors: Kristyn
authors: K
authors: Scheffel
authors: Caroline
authors: C
authors: Stetler
authors: Mary
authors: M
authors: Davis
authors: Dennis
authors: D
authors: Dickson
authors: Matthew
authors: M
authors: Jarpe
authors: Michael
authors: M
authors: DeTure
authors: Leonard
authors: L
authors: Petrucelli
mesh_terms: D000107:Acetylation; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism*; D020816:Amino Acid Motifs / Q000187:drug effects; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D057809:HEK293 Cells; D006367:HeLa Cells; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D051379:Mice; D010766:Phosphorylation; D055503:Protein Multimerization; D011743:Pyrimidines / Q000494:pharmacology; D016875:tau Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C054369:MAPT protein, human; C558298:Mapt protein, mouse; C583720:N-hydroxy-2-(1-phenylcycloproylamino)pyrimidine-5-carboxamide; D011743:Pyrimidines; D016875:tau Proteins; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
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