The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein

Publisher Website
Google Scholar
Abstract
One of the neuropathological hallmarks of Alzheimer's disease is the neurofibrillary tangle, which contains paired helical filaments (PHFs) composed of the microtubule-associated protein tau1,2. Tau is hyperphosphorylated in PHFs3,4,5,, and phosphorylation of tau abolishes its ability to bind microtubules and promote microtubule assembly6,7. Restoring the function of phosphorylated tau might prevent or reverse PHF formation in Alzheimer's disease. Phosphorylation on a serine or threonine that precedes proline (pS/T–P) alters the rate of prolyl isomerization and creates a binding site for the WW domain of the prolyl isomerase Pin1 (refs 8,9,10,11, 12,13,14). Pin1 specifically isomerizes pS/T–P bonds and regulates the function of mitotic phosphoproteins8,9,10,12. Here we show that Pin1 binds to only one pT–P motif in tau and co-purifies with PHFs, resulting in depletion of soluble Pin1 in the brains of Alzheimer's disease patients. Pin1 can restore the ability of phosphorylated tau to bind microtubules and promote microtubule assembly in vitro. As depletion of Pin1 induces mitotic arrest and apoptotic cell death8, sequestration of Pin1 into PHFs may contribute to neuronal death. These findings provide a new insight into the pathogenesis of Alzheimer's disease.