Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration

• Published in: Nature (London) 1999-12, Vol.402 (6762), p.615-622
• Main Authors: Tsai, Li-Huei, Patrick, Gentry N, Zukerberg, Lawrence, Nikolic, Margareta, de la Monte, Suzanne, Dikkes, Pieter
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Aged; Aged, 80 and over; Alzheimer Disease - enzymology; Alzheimer Disease - etiology; Alzheimer Disease - pathology; Alzheimer's disease; Animals; Apoptosis; Biological and medical sciences; Brain; Brain - enzymology; Central nervous system; Cloning, Molecular; COS Cells; Culture Techniques; Cyclin-Dependent Kinase 5; Cyclin-Dependent Kinases - metabolism; Cytoskeleton - metabolism; Cytoskeleton - pathology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Enzyme Activation; Enzyme Activators - metabolism; Enzyme Stability; Female; Humanities and Social Sciences; Humans; Immunohistochemistry; Male; Mammals; Matched-Pair Analysis; Medical sciences; Memory; Mice; Middle Aged; multidisciplinary; Nerve Tissue Proteins - metabolism; Nervous system; Neurofibrillary Tangles - enzymology; Neurology; Neurons; Neurons - pathology; p35 protein; Phosphorylation; Proteins; Rats; Rats, Sprague-Dawley; Science; Science (multidisciplinary); tau Proteins - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/45159

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.