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

Pei-Jung Lu, Gerburg Wulf, Xiao Zhen Zhou, Peter Davies and Kun Ping Lu ()
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Pei-Jung Lu: Cancer Biology Program, Beth Israel Deaconess Medical Center and Harvard Medical School
Gerburg Wulf: Cancer Biology Program, Beth Israel Deaconess Medical Center and Harvard Medical School
Xiao Zhen Zhou: Cancer Biology Program, Beth Israel Deaconess Medical Center and Harvard Medical School
Peter Davies: Albert Einstein College of Medicine
Kun Ping Lu: Cancer Biology Program, Beth Israel Deaconess Medical Center and Harvard Medical School

Nature, 1999, vol. 399, issue 6738, 784-788

Abstract: 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.

Date: 1999
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DOI: 10.1038/21650

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