DIA-MS Detect the Dephosphorylation of Tau by Phosphorylation Targeting Chimera (PhosTAC)

ABSTRACT: Microtubule-associated protein tau is essential for microtubule assembly and stabilization. Hyperphosphorylation of the microtubule-associated protein tau plays an important pathological role in the development of Alzheimer’s disease and other tauopathies, one of the greatest unmet demands in the clinic. In vivo studies using kinase inhibitors suggest that reducing tau phosphorylation levels has therapeutic potential; however, such approaches invariably showed limited benefits. We sought to develop our recently demonstrated Phosphorylation Targeting Chimera (PhosTAC) technology to specifically induce tau dephosphorylation. Herein, we use PhosTACs to recruit tau to PP2A, a native tau phosphatase. PhosTACs induced the formation of a stable ternary complex, leading to a rapid, efficient, and sustained dephosphorylation of tau, which also correlated the enhanced down regulation of tau. Mass spectrometry data validated that PhosTACs downregulated multiple phosphorylation sites of tau. We believe that PhosTACs present advantages over current strategies to modulate tau phosphorylation and represent a new avenue for disease-modifying therapies for tauopathies.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Hepatocyte, Hela Cell

DISEASE(S): Disease Free

SUBMITTER: Wenxue Li  

LAB HEAD: Yansheng Liu

PROVIDER: PXD037459 | Pride | 2023-03-16

REPOSITORIES: Pride