An acetylation-phosphorylation switch that regulates tau aggregation propensity and function [Neurobiology]

The aberrant accumulation of tau protein is a pathological hallmark of a class of neurodegenerative diseases known as tauopathies, including Alzheimer's disease (AD) and related dementias. On the basis of previous observations that tau is a direct substrate of histone deacetylase 6 (HDAC6), we sought to map all HDAC6-responsive sites in tau and determine how acetylation in a site-specific manner affects tau-s biophysical properties in vitro. Our findings indicate that several acetylation sites on tau are responsive to HDAC6 and that acetylation on Lys-321 (within a KCGS motif) is both essential for acetylation-mediated inhibition of tau aggregation in vitro and a molecular tactic for preventing phosphorylation on the downstream Ser-324 residue. To determine the functional consequence of this HDAC6- regulated phosphorylation event, we examined tau's ability to promote microtubule assembly and found that phosphorylation of Ser-324 interferes with the normal microtubule-stabilizing function of tau. Tau phosphorylation of Ser-324 (pSer-324) has not previously been evaluated in the context of tauopathy, and here we observed increased deposition of pSer-324-positive tau both in mouse models of tauopathy and in patients with AD. These findings uncover a novel acetylation--phosphorylation switch at Lys- 321/Ser-324 that coordinately regulates tau polymerization and function. As the disease relevance of this finding is evident, additional studies are needed to examine the role of pSer- 324 in tau pathobiology and to determine whether therapeutically modulating this acetylation--phosphorylation switch affects disease progression in vivo.

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