Pin1 has opposite effects on wild-type and P301L tau stability and tauopathy
Open Access
- 1 April 2008
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 118 (5), 1877-1889
- https://doi.org/10.1172/jci34308
Abstract
Tau pathology is a hallmark of many neurodegenerative diseases including Alzheimer disease (AD) and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). Genetic tau mutations can cause FTDP-17, and mice overexpressing tau mutants such as P301L tau are used as AD models. However, since no tau mutations are found in AD, it remains unclear how appropriate tau mutant mice are as an AD model. The prolyl isomerase Pin1 binds and isomerizes tau and has been implicated in protecting against neurodegeneration, but whether such Pin1 regulation is affected by tau mutations is unknown. Consistent with earlier findings that Pin1 KO induces tauopathy, here we demonstrate that Pin1 knockdown or KO increased WT tau protein stability in vitro and in mice and that Pin1 overexpression suppressed the tauopathy phenotype in WT tau transgenic mice. Unexpectedly, Pin1 knockdown or KO decreased P301L tau protein stability and abolished its robust tauopathy phenotype in mice. In contrast, Pin1 overexpression exacerbated the tauopathy phenotype in P301L tau mice. Thus, Pin1 has opposite effects on the tauopathy phenotype depending on whether the tau is WT or a P301L mutant, indicating the need for disease-specific therapies for tauopathies.This publication has 70 references indexed in Scilit:
- The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteinsJCI Insight, 2007
- Phosphorylation inhibits turnover of the tau protein by the proteasome: influence of RCAN1 and oxidative stressBiochemical Journal, 2006
- A Century of Alzheimer's DiseaseScience, 2006
- Pin1 Regulates Centrosome Duplication, and Its Overexpression Induces Centrosome Amplification, Chromosome Instability, and OncogenesisMolecular and Cellular Biology, 2006
- Age-Dependent Neurofibrillary Tangle Formation, Neuron Loss, and Memory Impairment in a Mouse Model of Human Tauopathy (P301L)Journal of Neuroscience, 2005
- GABAergic Excitation Promotes Neuronal Differentiation in Adult Hippocampal Progenitor CellsNeuron, 2005
- Tau Suppression in a Neurodegenerative Mouse Model Improves Memory FunctionScience, 2005
- Structural Basis for Phosphodependent Substrate Selection and Orientation by the SCFCdc4 Ubiquitin LigaseCell, 2003
- Tau and transgenic animal modelsBrain Research Reviews, 2001
- A human peptidyl–prolyl isomerase essential for regulation of mitosisNature, 1996