Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration

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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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Figure 1: Accumulation of p25 in brain lysates from patients with AD.
Figure 2: Immunohistochemistry of normal control and AD hippocampal sections.
Figure 3: a, Myristoylation sequence within p35 homologues is conserved.
Figure 4: Western blots of lysates from cycloheximide treatment half-life experiments of p35 and p25 (a) and the p35 G2A mutant (b) in transfected COS-7 cells.
Figure 5: Comparison of tau phosphorylation by p35/Cdk5 and p25/Cdk5.
Figure 6: Effects of the p25/Cdk5 kinase on the neuronal cytoskeleton.
Figure 7: The p25/Cdk5 kinase induces cytoskeletal collapse and nuclear fragmentation.
Figure 8: Quantification of nuclear fragmentation induced by the p25/Cdk5 kinase.


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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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Correspondence to Li-Huei Tsai.

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Patrick, G., Zukerberg, L., Nikolic, M. et al. Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402, 615–622 (1999) doi:10.1038/45159

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