Pin1 has opposite effects on wild-type and P301L tau stability and tauopathy
Jormay Lim, … , Virginia M.-Y. Lee, Kun Ping Lu
Jormay Lim, … , Virginia M.-Y. Lee, Kun Ping Lu
Published April 22, 2008
Citation Information: J Clin Invest. 2008;118(5):1877-1889. https://doi.org/10.1172/JCI34308.
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Research Article Neuroscience

Pin1 has opposite effects on wild-type and P301L tau stability and tauopathy

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.

Authors

Jormay Lim, Martin Balastik, Tae Ho Lee, Kazuhiro Nakamura, Yih-Cherng Liou, Anyang Sun, Greg Finn, Lucia Pastorino, Virginia M.-Y. Lee, Kun Ping Lu

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Figure 1

Pin1 KD in cells has opposite effects on the protein stability of WT tau and P301L tau; these effects depend on the presence of the Pin1-binding site in tau proteins.

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Pin1 KD in cells has opposite effects on the protein stability of WT tau...
SH-SY5Y cells were infected with Pin1 siRNA or control siRNA lentiviruses, followed by selection for stable cells with puromycin. Stable Pin1 KD or control SY5Y cells were transfected overnight with a WT tau expression construct in the presence or absence of a Pin1 expression construct (+Pin1 addback) (A and B), with a P301L tau construct in the presence or absence of a Pin1 construct (C and D), with a tau-T231A construct in the presence or absence of a Pin1 construct (E and F), or with a P301L tau-T231A construct in the presence or absence of a Pin1 construct (G and H). Cycloheximide was added to stop new protein synthesis and chased for indicated times in the absence or presence of the proteosome inhibitor MG132. Cells were harvested and cell lysates were fractionated by SDS-PAGE and analyzed by immunoblotting with Tau5, anti-Pin1, or anti-actin antibodies (A, C, E, and G). Tau levels were semiquantified from 3 different experiments using ImageQuant and normalized using actin as an internal control (B, D, F, and H). For comparison, tau levels at 0 (before the cycloheximide addition) were defined as 100%. The opposite effects of Pin1 KD on protein stability of WT tau and P301L tau were also obtained in HT1080 cells, as shown by dashed lines in B and D. Error bars represent SD.