Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration.
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.
Patrick
G N
GN
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Zukerberg
L
L
Nikolic
M
M
de la Monte
S
S
Dikkes
P
P
Tsai
L H
LH
D016475:3T3 Cells; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000201:enzymology; D019556:COS Cells; D003001:Cloning, Molecular; D046508:Culture Techniques; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000378:metabolism; D004795:Enzyme Stability; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D016555:Matched-Pair Analysis; D051379:Mice; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016874:Neurofibrillary Tangles / Q000201:enzymology; D009474:Neurons / Q000473:pathology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D016875:tau Proteins / Q000378:metabolism
D020536:Enzyme Activators; D009419:Nerve Tissue Proteins; C089495:neuronal Cdk5 activator (p25-p35); D016875:tau Proteins; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; C495906:Cdk5 protein, mouse; C495907:Cdk5 protein, rat; D018844:Cyclin-Dependent Kinases