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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

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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 10

A model for the diametrically opposite impact of Pin1 on tau levels and tauopathy phenotype depending on whether the tau is WT or P301L mutant.

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A model for the diametrically opposite impact of Pin1 on tau levels and ...
Our results have shown that Pin1 has the opposite impact on the ability to induce the tauopathy phenotype. Although both WT tau and P301L tau are likely phosphorylated on certain Ser/Thr-Pro motifs, such as the Thr231-Pro motif in trans by upstream kinases, the pThr231-Pro motif in WT tau might have a tendency to be in the cis conformation due to local structural constraints. Pin1 overexpression might greatly accelerate the cis to trans isomerization to promote tau degradation (A). When Pin1 is inhibited, the cis pThr231-Pro motif might not be isomerized to trans in a timely manner, which might inhibit tau degradation (B). However, in the case of P301L tau, the mutation might somehow change tau conformation so that the pThr231-Pro motif might have a tendency to be in trans, which might promote P301L tau degradation when Pin1 is inhibited (C). However, Pin1 overexpression might accelerate the trans to cis isomerization to inhibit P301L tau degradation (D). PPases, protein phosphatases.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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