Acetylation of the KXGS motifs in tau is a critical determinant in modulation of tau aggregation and clearance
Oxford University Press, 2014
academicJournal
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.
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Acetylation of the KXGS motifs in tau is a critical determinant in modulation of tau aggregation and clearance
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Autor/in / Beteiligte Person: | Cook, Casey ; Carlomagno, Yari ; Gendron, Tania F. ; Dunmore, Judy ; Scheffel, Kristyn ; Stetler, Caroline ; Davis, Mary ; Dickson, Dennis ; Jarpe, Matthew ; DeTure, Michael ; Petrucelli, Leonard |
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Veröffentlichung: | Oxford University Press, 2014 |
Medientyp: | academicJournal |
DOI: | 10.1093/hmg/ddt402 |
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