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      Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration.

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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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          Author and article information

          Journal
          Nature
          Nature
          Springer Science and Business Media LLC
          0028-0836
          0028-0836
          Dec 09 1999
          : 402
          : 6762
          Affiliations
          [1 ] Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
          Article
          10.1038/45159
          10604467
          efc7e09a-3a31-47b5-bcef-8b20badd8556
          History

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