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 and Kun Ping Lu ()
Additional contact information
Yih-Cherng Liou: Harvard Medical School
Anyang Sun: Harvard Medical School
Akihide Ryo: Harvard Medical School
Xiao Zhen Zhou: Harvard Medical School
Zhao-Xue Yu: Emory University
Han-Kuei Huang: Salk Institute
Takafumi Uchida: Tohoku University
Roderick Bronson: Tufts University School of Veterinary Medicine
Guoying Bing: University of Kentucky
Xiaojiang Li: Emory University
Tony Hunter: Salk Institute
Kun Ping Lu: Harvard Medical School

Nature, 2003, vol. 424, issue 6948, 556-561

Abstract: Abstract The neuropathological hallmarks of Alzheimer's disease and other tauopathies include senile plaques and/or neurofibrillary tangles1,2,3,4. Although mouse models have been created by overexpressing specific proteins including β-amyloid precursor protein, presenilin and tau1,2,3,4,5,6,7,8,9,10, 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 disease11,12,13,14. Notably, these phospho(Ser/Thr)-Pro motifs exist in two distinct conformations, whose conversion in some proteins is catalysed by the Pin1 prolyl isomerase15,16,17. 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 neurodegeneration14,18,19; 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.

Date: 2003
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DOI: 10.1038/nature01832

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