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

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.

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Figure 1: Inverse correlation of Pin1 expression with predicted neuronal vulnerability in normally aged brains and actual neurofibrillary degeneration in AD.
Figure 2: Age-dependent motor and behavioural deficits in Pin1-/- mice.
Figure 3: Age-dependent neuronal degeneration in Pin1-/- mice.
Figure 4: MPM-2 induction, tau hyperphosphorylation, NFT-specific conformations and reduced phosphatase activity toward the phospho(Ser/Thr)-Pro motif in Pin1-/- brain.
Figure 5: NFT-like pathologies and tau filaments in Pin1-/- neurons.

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References

  1. Selkoe, D. J. The cell biology of β-amyloid precursor protein and presenilin in Alzheimer's disease. Trends Cell Biol. 8, 447–453 (1998)

    Article  CAS  Google Scholar 

  2. Mandelkow, E. M. & Mandelkow, E. Tau in Alzheimer's disease. Trends Cell Biol. 8, 425–427 (1998)

    Article  CAS  Google Scholar 

  3. Lee, V. M., Goedert, M. & Trojanowski, J. Q. Neurodegenerative tauopathies. Annu. Rev. Neurosci. 24, 1121–1159 (2001)

    Article  CAS  Google Scholar 

  4. Wong, P. C., Cai, H., Borchelt, D. R. & Price, D. L. Genetically engineered mouse models of neurodegenerative diseases. Nature Neurosci. 5, 633–639 (2002)

    Article  CAS  Google Scholar 

  5. Ishihara, T. et al. Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform. Neuron 24, 751–762 (1999)

    Article  CAS  Google Scholar 

  6. Lewis, J. et al. Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nature Genet. 25, 402–405 (2000)

    Article  CAS  Google Scholar 

  7. Gotz, J., Chen, F., Barmettler, R. & Nitsch, R. M. Tau filament formation in transgenic mice expressing P301L tau. J. Biol. Chem. 276, 529–534 (2001)

    Article  CAS  Google Scholar 

  8. Lewis, J. et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293, 1487–1491 (2001)

    Article  ADS  CAS  Google Scholar 

  9. Gotz, J., Chen, F., van Dorpe, J. & Nitsch, R. M. Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Aβ42 fibrils. Science 293, 1491–1495 (2001)

    Article  ADS  CAS  Google Scholar 

  10. Allen, B. et al. Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J. Neurosci. 22, 9340–9351 (2002)

    Article  CAS  Google Scholar 

  11. Bancher, C. et al. Accumulation of abnormally phosphorylated tau precedes the formation of neurofibrillary tangles in Alzheimer's disease. Brain Res. 477, 90–99 (1989)

    Article  CAS  Google Scholar 

  12. Preuss, U. & Mandelkow, E. M. Mitotic phosphorylation of tau protein in neuronal cell lines resembles phosphorylation in Alzheimer's disease. Eur. J. Cell Biol. 76, 176–184 (1998)

    Article  CAS  Google Scholar 

  13. Vincent, I., Zheng, J. H., Dickson, D. W., Kress, Y. & Davies, P. Mitotic phosphoepitopes precede paired helical filaments in Alzheimer's disease. Neurobiol. Aging 19, 287–296 (1998)

    Article  CAS  Google Scholar 

  14. Lu, K. P., Liou, Y. C. & Vincent, I. Proline-directed phosphorylation and isomerization in mitotic regulation and in Alzheimer's disease. BioEssays 25, 174–181 (2003)

    Article  CAS  Google Scholar 

  15. Lu, K. P., Hanes, S. D. & Hunter, T. A human peptidyl-prolyl isomerase essential for regulation of mitosis. Nature 380, 544–547 (1996)

    Article  ADS  CAS  Google Scholar 

  16. Yaffe, M. B. et al. Sequence-specific and phosphorylation-dependent proline isomerization: a potential mitotic regulatory mechanism. Science 278, 1957–1960 (1997)

    Article  ADS  CAS  Google Scholar 

  17. Lu, K. P., Liou, Y. C. & Zhou, X. Z. Pinning down the proline-directed phosphorylation signaling. Trends Cell Biol. 12, 164–172 (2002)

    Article  CAS  Google Scholar 

  18. Lu, P. J., Wulf, G., Zhou, X. Z., Davies, P. & Lu, K. P. The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein. Nature 399, 784–788 (1999)

    Article  ADS  CAS  Google Scholar 

  19. Zhou, X. Z. et al. Pin1-dependent prolyl isomerization regulates dephosphorylation of Cdc25C and tau proteins. Mol. Cell 6, 873–883 (2000)

    Article  CAS  Google Scholar 

  20. Holzer, M. et al. Inverse association of Pin1 and tau accumulation in Alzheimer's disease hippocampus. Acta Neuropathol. 104, 471–481 (2002)

    CAS  PubMed  Google Scholar 

  21. Davies, D. C., Horwood, N., Isaacs, S. L. & Mann, D. M. The effect of age and Alzheimer's disease on pyramidal neuron density in the individual fields of the hippocampal formation. Acta Neuropathol. 83, 510–517 (1992)

    Article  CAS  Google Scholar 

  22. Liou, Y. C. et al. Loss of Pin1 function in the mouse resembles the cyclin D1-null phenotypes. Proc. Natl Acad. Sci. USA 99, 1335–1340 (2002)

    Article  ADS  CAS  Google Scholar 

  23. Husseman, J. W., Nochlin, D. & Vincent, I. Mitotic activation: a convergent mechanism for a cohort of neurodegenerative diseases. Neurobiol. Aging 21, 815–828 (2000)

    Article  CAS  Google Scholar 

  24. Kins, S. et al. Reduced protein phosphatase 2A activity induces hyperphosphorylation and altered compartmentalization of tau in transgenic mice. J. Biol. Chem. 276, 38193–38200 (2001)

    CAS  PubMed  Google Scholar 

  25. Wolozin, B. L., Pruchnicki, A., Dickson, D. W. & Davies, P. A neuronal antigen in the brains of Alzheimer patients. Science 232, 648–650 (1986)

    Article  ADS  CAS  Google Scholar 

  26. Lee, V. M., Balin, B. J., Otvos, L. Jr & Trojanowski, J. Q. A68: a major subunit of paired helical filaments and derivatized forms of normal Tau. Science 251, 675–678 (1991)

    Article  ADS  CAS  Google Scholar 

  27. Gordon-Krajcer, W., Yang, L. & Ksiezak-Reding, H. Conformation of paired helical filaments blocks dephosphorylation of epitopes shared with fetal tau except Ser199/202 and Ser202/Thr205. Brain Res. 856, 163–175 (2000)

    Article  CAS  Google Scholar 

  28. Fujimori, F., Takahashi, K., Uchida, C. & Uchida, T . Mice lacking Pin1 develop normally, but are defective in entering cell cycle from G90) arrest. Biochem. Biophys. Res. Commun 265, 658–663 (1999)

    Article  CAS  Google Scholar 

  29. Patrick, G. N. et al. Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402, 615–622 (1999)

    Article  ADS  CAS  Google Scholar 

  30. Lucas, J. J. et al. Decreased nuclear β-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3β conditional transgenic mice. EMBO J. 20, 27–39 (2001)

    Article  CAS  Google Scholar 

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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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Correspondence to Kun Ping Lu.

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Kun Ping Lu and Tony Hunter are consultants to Pintex.

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Liou, YC., Sun, A., Ryo, A. et al. Role of the prolyl isomerase Pin1 in protecting against age-dependent neurodegeneration. Nature 424, 556–561 (2003). https://doi.org/10.1038/nature01832

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