Title

Acetylation of tau inhibits its degradation and contributes to tauopathy.

Journal

Neuron

Volume

67

Issue

None

Pages

953-66

Date

2010-09-23

Authors

Min SW | Gan L | Masliah E | Zhou Y | Cho SH | Cole PA | Haroutunian V | Huang EJ | Meyers D | Mukherjee C | Ott M | Schroeder S | Seeley WW | Shen Y

Next, we treated primary neurons with C646, a pyrazolone-containing small-molecule inhibitor of p300 with a Ki of 400 nM (Bowers et al., 2010). Under cell-free conditions, C646 at 10 μM inhibits p300 in a highly selective manner (86% inhibition vs. <10% for the six other acetyltransferases) (Bowers et al., 2010). Inhibition of p300 with C646 (20 μM) drastically reduced levels of ac-tau in primary neurons within 8 h.

Thus, the increase in ac-tau induced by SIRT1 deficiency is accompanied by accumulation of pathogenic p-tau in primary neurons. In mouse brains, deleting SIRT1, which elevated ac-tau, also increased AT8-positive p-tau.

Incubation with p300, not pCAF, led to tau acetylation, while both p300 and pCAF were active in transferring acetyl groups to histones as expected (Figure 1A). A few putative acetylated lysines were in the N- and C- terminal regions; 13 were in microtubule-binding domains (Figure 1B and Table-S1). Putative acetylated N-terminal lysines (e.g., lysines 163, 174, and 180) appeared to be acetylated in all MS analyses. Those in the microtubule-binding domains appeared to be acetylated in a subset of MS analyses, suggesting variable acetylation at these sites in vitro.

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