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Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration

Author

Listed:
  • Gentry N. Patrick

    (Harvard Medical School)

  • Lawrence Zukerberg

    (Harvard Medical School
    Massachusetts General Hospital)

  • Margareta Nikolic

    (Harvard Medical School
    King's College London)

  • Suzanne de la Monte

    (Massachusetts General Hospital
    Massachusetts General Hospital—East Cancer Center)

  • Pieter Dikkes

    (Children's Hospital)

  • Li-Huei Tsai

    (Harvard Medical School
    Howard Hughes Medical Institute)

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.

Suggested Citation

  • Gentry N. Patrick & Lawrence Zukerberg & Margareta Nikolic & Suzanne de la Monte & Pieter Dikkes & Li-Huei Tsai, 1999. "Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration," Nature, Nature, vol. 402(6762), pages 615-622, December.
    • Handle: RePEc:nat:nature:v:402:y:1999:i:6762:d:10.1038_45159
    DOI: 10.1038/45159
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    Cited by:

    1. Layla Al-Nakkash & Daniel Mason & Niamatullah Ismail & Taylor Bowman & John Ahlert & Maxwell Rubin & Emma Smith & Abigail Rosander & Tom L. Broderick, 2022. "Exercise Training Prevents the Loss of Wall Thickness and Lowers Expression of Alzheimer’s Related Proteins in 3xTg Mouse Jejunum," IJERPH, MDPI, vol. 19(21), pages 1-13, October.
    2. Xu Han & Keping Chen, 2020. "Phosphorylation of The Tau Protein in Neurodegenerative Disease," Biomedical Journal of Scientific & Technical Research, Biomedical Research Network+, LLC, vol. 26(4), pages 20184-20196, March.

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