Acetylation of the KXGS motifs in tau is a critical determinant in modulation of tau aggregation and clearance
In: Human Molecular Genetics, Jg. 23 (2013-08-01), Heft 1, S. 104-116
Online
unknown
Zugriff:
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.
Titel: |
Acetylation of the KXGS motifs in tau is a critical determinant in modulation of tau aggregation and clearance
|
---|---|
Autor/in / Beteiligte Person: | DeTure, Michael ; Davis, Mary D. ; Stetler, Caroline ; Petrucelli, Leonard ; Cook, Casey ; Dickson, Dennis W. ; Scheffel, Kristyn ; Jarpe, Matthew ; Dunmore, Judy ; Gendron, Tania F. ; Carlomagno, Yari |
Link: | |
Zeitschrift: | Human Molecular Genetics, Jg. 23 (2013-08-01), Heft 1, S. 104-116 |
Veröffentlichung: | Oxford University Press, 2013 |
Medientyp: | unknown |
ISSN: | 1460-2083 (print) ; 0964-6906 (print) |
Schlagwort: |
|
Sonstiges: |
|