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Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration

Nature volume 402, pages 615622 (09 December 1999) | Download Citation

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Abstract

Cyclin-dependent kinase 5 (Cdk5) is required for proper development of the mammalian central nervous system. To be activated, Cdk5 has to associate with its regulatory subunit, p35. We have found that p25, a truncated form of p35, accumulates in neurons in the brains of patients with Alzheimer's disease. This accumulation correlates with an increase in Cdk5 kinase activity. Unlike p35, p25 is not readily degraded, and binding of p25 to Cdk5 constitutively activates Cdk5, changes its cellular location and alters its substrate specificity. In vivo the p25/Cdk5 complex hyperphosphorylates tau, which reduces tau's ability to associate with microtubules. Moreover, expression of the p25/Cdk5 complex in cultured primary neurons induces cytoskeletal disruption, morphological degeneration and apoptosis. These findings indicate that cleavage of p35, followed by accumulation of p25, may be involved in the pathogenesis of cytoskeletal abnormalities and neuronal death in neurodegenerative diseases.

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Acknowledgements

We thank D. Auprin, P. Davies, X. He, R. Neve and J. P. Vonsattel for reagents; Y. Zhou for antibody preparations; D. Smith for help with microscopy; and M. Greenberg, P. Lu, Y. Shi, G. Gill, Y. T. Kwon, D. Smith, V. Tannoch and J. Volker for critical reading of this manuscript. This work was partially supported by NIH grants to L.-H.T. L.-H.T. is an assistant investigator of the Howard Hughes Medical Institute, a Rita Allen Foundation scholar and a recipient of an Ester A. and Joseph Klingenstein Fund award.

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Author notes

    • Margareta Nikolic

    Present address: Molecular Neurobiology Group, King's College London, London SE1 9RT, UK

Affiliations

  1. *Department of Pathology, Harvard Medical School and Howard Hughes Medical Institute, 200 Longwood Avenue, Boston, Massachusetts 02115, USA

    • Li-Huei Tsai
  2. †Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA

    • Lawrence Zukerberg
    •  & Suzanne de la Monte
  3. §Massachusetts General Hospital—East Cancer Center, Charlestown, Massachusetts 02119, USA

    • Suzanne de la Monte
  4. Department of Neurology, Children's Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115, USA

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Correspondence to Li-Huei Tsai.

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https://doi.org/10.1038/45159

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