Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein

Nature volume 399, pages 784–788 (1999)Cite this article

Abstract

One of the neuropathological hallmarks of Alzheimer's disease is the neurofibrillary tangle, which contains paired helical filaments (PHFs) composed of the microtubule-associated protein tau1,2. Tau is hyperphosphorylated in PHFs3,4,5,, and phosphorylation of tau abolishes its ability to bind microtubules and promote microtubule assembly6,7. Restoring the function of phosphorylated tau might prevent or reverse PHF formation in Alzheimer's disease. Phosphorylation on a serine or threonine that precedes proline (pS/T–P) alters the rate of prolyl isomerization and creates a binding site for the WW domain of the prolyl isomerase Pin1 (refs 8,9,10,11, 12,13,14). Pin1 specifically isomerizes pS/T–P bonds and regulates the function of mitotic phosphoproteins8,9,10,12. Here we show that Pin1 binds to only one pT–P motif in tau and co-purifies with PHFs, resulting in depletion of soluble Pin1 in the brains of Alzheimer's disease patients. Pin1 can restore the ability of phosphorylated tau to bind microtubules and promote microtubule assembly in vitro. As depletion of Pin1 induces mitotic arrest and apoptotic cell death8, sequestration of Pin1 into PHFs may contribute to neuronal death. These findings provide a new insight into the pathogenesis of Alzheimer's disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Interaction of Pin1 with pTau and Alzheimer's disease tau, but not with pTauT231A.
Figure 2: Localization of Pin1 in normal and AD brains and competition of Pin1 binding by pT231 antibody.
Figure 3: Depletion of soluble Pin1 in AD brains.
Figure 4: Characterization of the Pin1–tau interaction.
Figure 5: Restoration of function of pTau by Pin1, but not its mutants or cyclophilin.

Similar content being viewed by others

References

  1. Kosik, K. S., Qiu, W. Q. & Greenberg, S. Cellular signaling pathways and cytoskeletal organization. Ann. NY Acad. Sci. 777, 114– 120 (1996).

    Article  ADS  CAS  Google Scholar 

  2. Spillantini, M. G. & Goedert, M. Tau protein pathology in neurodegenerative diseases. Trends Neurosci. 21, 428–433 (1998).

    Article  CAS  Google Scholar 

  3. Lee, V. M., Balin, B. J., Otvos, L. J & 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 

  4. Goedert, M., Spillantini, M. G., Cairns, N. J. & Crowther, R. A. Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron. 8, 159 –168 (1992).

    Article  CAS  Google Scholar 

  5. Greenberg, S. G., Davies, P., Schein, J. D. & Binder, L. I. Hydrofluoric acid-treated tau PPHF proteins display the same biochemical properties as normal tau. J. Biol. Chem. 267, 564– 569 (1992).

    CAS  PubMed  Google Scholar 

  6. Bramblett, G. T. et al. Abnormal tau phosphorylation at Ser396 in Alzheimer's disease recapitulates development and contributes to reduced microtubule binding. Neuron 10, 1089–1099 (1993).

    Article  CAS  Google Scholar 

  7. Yoshida, H. & Ihara, Y. Tau in paired helical filaments is functionally distinct from fetal tau: assembly incompetence of paired helical filament-tau. J. Neurochem. 61, 1183– 1186 (1993).

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  9. Ranganathan, R., Lu, K. P., Hunter, T. & Noel, J. P. Structural and functional analysis of the mitotic peptidyl-prolyl isomerase Pin1 suggests that substrate recognition is phosphorylation dependent. Cell 89, 875–886 (1997).

    Article  CAS  Google Scholar 

  10. 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 

  11. Schutkowski, M. et al. Role of phosphorylation in determining the backbone dynamics of the serine/threonine-proline motif and Pin1 substrate recognition. Biochemistry 37, 5566–5575 (1998).

    Article  CAS  Google Scholar 

  12. Shen, M., Stukenberg, P. T., Kirschner, M. W. & Lu, K. P. The essential mitotic peptidyl-prolyl isomerase Pin1 binds and regulates mitosis-specific phosphoproteins. Genes Dev. 12, 706– 720 (1998).

    Article  CAS  Google Scholar 

  13. Lu, P. J., Zhou, X. Z., Shen, M. & Lu, K. P. Function of WW domains as phosphoserine or phosphothreonine-binding modules. Science 283, 1325–1328 (1999).

    Article  ADS  CAS  Google Scholar 

  14. Lu, K. P. Phosphorylation-dependent prolyl isomerization: a novel cell cycle regulatory mechanism. Prog. Cell Cycle Res.(in the press).

  15. Crenshaw, D. G., Yang, J., Means, A. R. & Kornbluth, S. The mitotic peptidyl-prolyl isomerase, Pin1, interacts with Cdc25 and Plx1. EMBO J. 17, 1315–1327 ( 1998).

    Article  CAS  Google Scholar 

  16. Illenberger, S. et al. The endogenous and cell cycle-dependent phosphorylation of tau protein in living cells: implications for Alzheimer's disease. Mol. Biol. Cell 9, 1495–1512 (1998).

    Article  CAS  Google Scholar 

  17. Vincent, I., Rosado, M. & Davies, P. Mitotic mechanisms in Alzheimer's disease? J. Cell Biol. 132, 413–425 (1996).

    Article  CAS  Google Scholar 

  18. Vincent, I., Jicha, G., Rosado, M. & Dickson, D. W. Aberrant expression of mitotic cdc2/cyclin B1 kinase in degenerating neurons of Alzheimer's disease brain. J. Neurosci. 17, 3588– 3598 (1997).

    Article  CAS  Google Scholar 

  19. Nagy, Z., Esiri, M. M. & Smith, A. D. Expression of cell division markers in the hippocampus in Alzheimer's disease and other neurodegenerative conditions. Acta Neuropathol. (Berl.) 93, 294– 300 (1997).

    Article  CAS  Google Scholar 

  20. Kondratick, C. M. & Vandre, D. D. Alzheimer's disease neurofibrillary tangles contain mitosis-specific phosphoepitopes. J. Neurochem. 67, 2405– 2416 (1996).

    Article  CAS  Google Scholar 

  21. 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 

  22. Vincent, I. J. & Davies, P. Aprotein kinase associated with paired helical filaments in Alzheimer disease. Proc. Natl Acad. Sci. USA 89, 2878– 2882 (1992).

    Article  ADS  CAS  Google Scholar 

  23. Jicha, G. A. et al. Aconformation- and phosphorylation-dependent antibody recognizing the paired helical filaments of Alzheimer's disease. J. Neurochem. 69, 2087–2095 ( 1997).

    Article  CAS  Google Scholar 

  24. Hutton, M. et al. Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393, 702–705 (1998).

    Article  ADS  CAS  Google Scholar 

  25. Clark, L. N. et al. Pathogenic implications of mutations in the tau gene in palido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17. Proc. Natl Acad. Sci. USA 95, 13103– 13107 (1998).

    Article  ADS  CAS  Google Scholar 

  26. Spillantini, M. G. et al. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc. Natl Acad. Sci. USA 95, 7737–7741 (1998).

    Article  ADS  CAS  Google Scholar 

  27. Iqbal, K., Zaidi, T., Bancher, C. & Grundke-Iqbal, I. Alzheimer paired helical filaments. Restoration of the biological activity by dephosphorylation. FEBS Lett. 349, 104–108 (1994).

    Article  CAS  Google Scholar 

  28. Alonso, A. C., Zaidi, T., Grundke-Iqbal, I. & Iqbal, K. Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease. Proc. Natl Acad. Sci. USA 91, 5562–5566 (1994).

    Article  ADS  CAS  Google Scholar 

  29. Spillantini, M. G., Bird, T. D. & Ghetti, B. Frontotemporal dementia and Parkinsonism linked to chromosome 17: a new group of tauopathies. Brain Pathol. 8, 387–402 (1998).

    Article  CAS  Google Scholar 

  30. Hong, M. et al. Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science 282, 1914 –1917 (1998).

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank B. Neel, L. Cantley, C. S. Chen, G. Lee and X. D. Fu for constructive comments. P.-J.L. and G.W. are fellows of Leukemia Society of America and DOE Breast Cancer Research Program, respectively. K.P.L. is a Pew Scholar and a Leukemia Society of America Scholar. This study was supported by NIH grants to P.D. and K.P.L.

Author information

Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Medicine, Cancer Biology Program, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, 02215, Massachusetts , USA

    Pei-Jung Lu, Gerburg Wulf, Xiao Zhen Zhou & Kun Ping Lu

  2. Department of Pathology, Albert Einstein College of Medicine, Bronx, 10461 , New York, USA

    Peter Davies

Authors
  1. Pei-Jung Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gerburg Wulf
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiao Zhen Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peter Davies
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kun Ping Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kun Ping Lu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lu, PJ., Wulf, G., Zhou, X. et al. The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein. Nature 399, 784–788 (1999). https://doi.org/10.1038/21650

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/21650

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing