Summary Neurodegenerative tauopathies characterized by hyperphosphorylated tau include frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and Alzheimer's disease (AD). Reducing tau levels improves cognitive function in mouse models of AD and FTDP-17, but the mechanisms regulating the turnover of pathogenic tau are unknown. We found that tau is acetylated and that tau acetylation prevents degradation of phosphorylated tau (p-tau). Using two antibodies specific for acetylated tau, we showed that tau acetylation is elevated in patients at early and moderate Braak stages of tauopathy. Histone acetyltransferase p300 was involved in tau acetylation and the class III protein deacetylase SIRT1 in deacetylation. Deleting SIRT1 enhanced levels of acetylated-tau and pathogenic forms of p-tau in vivo, likely by blocking proteasome-mediated degradation. Inhibiting p300 with a small molecule promoted tau deacetylation and eliminated p-tau associated with tauopathy. Modulating tau acetylation could be a new therapeutic strategy to reduce tau-mediated neurodegeneration.

During synaptic vesicle fusion, the SNARE-protein syntaxin-1 exhibits two conformations that both bind to Munc18-1: a ‘closed’ conformation outside the SNARE-complex, and an ‘open’ conformation in the SNARE-complex. Whereas SNARE-complexes containing ‘open’ syntaxin-1 and Munc18-1 are essential for exocytosis, the significance of ‘closed’ syntaxin-1 is unknown. Here, we generated knockin/knockout mice that expressed only ‘open’ syntaxin-1B. Syntaxin-1BOpen mice were viable, but succumbed to generalized seizures at 2-3 months of age. Binding of Munc18-1 to syntaxin-1 was impaired in syntaxin-1BOpen synapses, and the size of the readily-releasable vesicle pool was decreased, whereas the rate of synaptic vesicle fusion was dramatically enhanced. Thus, the closed conformation of syntaxin-1 gates the initiation of the synaptic vesicle fusion reaction, which is then mediated by SNARE-complex/Munc18-1 assemblies.