Regulation of Cyclin-Dependent Kinase 5 (Cdk5) With Special Emphasis on Changes Occurring During Neuronal Cell Death

Neuronal loss occurs in several neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease, as well as following acute insults, such as brain ischemia and trauma. In general, cell death can be categorized into two main types, apoptosis and necrosis, which are differentiated by distinct morphological and biochemical features. Cell death of neurons possesses special characteristics that are still inadequately understood. Deregulation of the cyclin-dependent kinase 5 (cdk5) has been suggested to have several consequences that might contribute to the course of neuronal death in both acute and chronic conditions. This deregulation could involve proteolytic cleavage of the cdk5 activator protein p35 to a p25fragment by the calcium-activated calpain-protease. Nevertheless, there are wide gaps in our understanding on the regulation of cdk5, which hampers the evaluation of the possible involvement of cdk5 in neuronal death. The aim of this study was to investigate the regulation of cdk5, in particular during the course of neuronal cell death, and also to evaluate the possible relationship between cdk5 and phosphorylation of the microtubule-associated protein tau. When cultured rat hippocampal neurons were subjected to various apoptosis-inducing compounds, one characteristic response was a decrease in the protein levels of p35, p25, and cdk5 as well as a reduction in the cdk5 activity and tau phosphorylation. Toxicity caused by the neurotransmitter glutamate, or by calcium ionophores, was associated with a rapid calpain-mediated cleavage of p35, and an increase in the cdk5 activity. Unexpectedly, tau phosphorylation was concomitantly decreased. Both N-methyl-D-aspartate (NMDA) and non-NMDA classes of glutamate receptors were able to induce calpain-mediated p35 cleavage in the cultured neurons. However, the NMDA receptors predominantly mediated the effect of glutamate in neurons under normal culture conditions. A significant proportion of the p35 protein was detected in a phosphorylated state in rat brain tissue. Phosphorylation of p35 appeared to affect its proteolytic degradation by the proteasome, as well as the calpain-mediated cleavage of p35 to p25. In conclusion, the regulation of cdk5 is altered during the process of neuronal death. The neurotransmitter glutamate could be an especially relevant inducer of the putative cdk5associated mechanisms of cell death. However, the changes in cdk5 during neuronal death do not seem to be invariably linked to the phosphorylation status of tau protein. National Library of Medicine Classification: QU 57, QU 135, QU 143, QU 325, QU 375, QY 60.R6, WL 102.5, WL 104, WL 314, WL 359 Medical Subject Headings: adenosine triphosphate; brain chemistry; calpain; cell death; cells, cultured; cyclin-dependent kinase 5; cysteine endopeptidases; dipeptides; enzyme activation; enzyme inhibitors; glutamic acid; hippocampus/cytology; hippocampus/drug effects; nerve tissue proteins; neurodegenerative diseases; neurons/drug effects; neurons/metabolism; phosphorylation; rats; receptors, glutamate; tau proteins To Elina, Elias, and Martta