Role of the prolyl isomerase Pin1 in protecting against age-dependent neurodegeneration

Yih Cherng Liou, Anyang Sun, Akihide Ryo, Xiao Zhen Zhou, Zhao Xue Yu, Han Kuei Huang, Takafumi Uchida, Roderick Bronson, Guoying Bing, Xiaojiang Li, Tony Hunter, Kun Ping Lu

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390 Scopus citations


The neuropathological hallmarks of Alzheimer's disease and other tauopathies include senile plaques and/or neurofibrillary tangles. Although mouse models have been created by overexpressing specific proteins including β-amyloid precursor protein, presenilin and tau, no model has been generated by gene knockout. Phosphorylation of tau and other proteins on serine or threonine residues preceding proline seems to precede tangle formation and neurodegeneration in Alzheimer's disease. Notably, these phospho(Ser/Thr)-Pro motifs exist in two distinct conformations, whose conversion in some proteins is catalysed by the Pin1 prolyl isomerase. Pin1 activity can directly restore the conformation and function of phosphorylated tau or it can do so indirectly by promoting its dephosphorylation, which suggests that Pin1 is involved in neurodegeneration; however, genetic evidence is lacking. Here we show that Pin1 expression is inversely correlated with predicted neuronal vulnerability and actual neurofibrillary degeneration in Alzheimer's disease. Pin1 knockout in mice causes progressive age-dependent neuropathy characterized by motor and behavioural deficits, tau hyperphosphorylation, tau filament formation and neuronal degeneration. Thus, Pin1 is pivotal in protecting against age-dependent neurodegeneration, providing insight into the pathogenesis and treatment of Alzheimer's disease and other tauopathies.

Original languageEnglish
Pages (from-to)556-561
Number of pages6
Issue number6948
StatePublished - Jul 31 2003

Bibliographical note

Funding Information:
Acknowledgements We thank F. Gage, L. Cantley, B. Neel and K. Kosik for comments on the manuscript; W. Markesbery for human brain samples; P. Davies for tau antibodies; and G. Liu, M. Liu and M. Ericsson for technical assistance. Y.-C.L. is a Fellow of the Canadian Institutes of Health Research, A.R. is a Special Fellow of the Leukemia and Lymphoma Society; T.H. is a Frank and Else Schilling American Cancer Society Research Professor; and K.P.L. is a Pew Scholar and a Leukemia and Lymphoma Society Scholar. This study was supported by NIH grants to G.B., X.J.L., T.H. and K.P.L.

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