Cyclin-dependent kinase 5--a neuronal killer?
In dividing cells, cyclin-dependent kinases (Cdks) are cell cycle-associated protein kinases that regulate proliferation, differentiation, senescence, and apoptosis. In neurons that no longer divide, deregulation of Cdks, especially Cdk5, occurs in many neurological disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD). Cdk5 is a unique member of the Cdk family because it does not play a critical role in cell cycle progression, and it is not activated by a cyclin. Instead, Cdk5 normally is activated by the regulatory protein p35. This Cdk5/p35 activity has emerged as an important regulator of proper development of the mammalian central nervous system. In vitro studies suggest that aberrant activation of Cdk5 by an endogenous truncated version (p25) of p35 might be a key event in the process of neurodegeneration. One enzyme responsible for cleavage of p35 to form p25 is calpain, a calcium-activated protease that has been shown to be involved in neuronal cell death. Recent studies provided important in vivo evidence that hyperactivation and redistribution of Cdk5 by p25 plays an essential role in the phosphorylation of "pathological" substrates (such as tau) and the cell death of neurons in experimental models of AD and PD. Because amyloid beta peptide, the primary neurotoxic component of amyloid plaques in AD, has been shown to increase the conversion of p35 to p25, aberrant activation of Cdk5 by p25 might be a pathway connecting amyloid beta toxicity to tau hyperphosphorylation in AD.
Guo
Qing
Q
Department of Physiology, University of Oklahoma Health Sciences Center, College of Medicine, Oklahoma City, OK 73104, USA. qing-guo@ouhsc.edu
D000818:Animals; D016923:Cell Death / Q000502:physiology; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000502:physiology*; D006801:Humans; D019636:Neurodegenerative Diseases / Q000201:enzymology* / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000201:enzymology*
D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; D018844:Cyclin-Dependent Kinases