Cyclin-dependent kinase 5 (Cdk5), a proline-directed serine/threonine kinase, plays essential roles in CNS development. Its activation requires the association with its neuron-specific regulator, p35 or p39. Recent evidence reveals that deregulation of Cdk5 is linked to various neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, which are characterized by loss of selective neuronal populations. However, the molecular mechanisms implicated in the regulation of Cdk5 activity during neuronal apoptosis remain elusive. It has recently been shown that Cdk5RAP1, a protein that interacts with p35, is able to inhibit Cdk5/p35 kinase activity in vitro. It is thus of interest to examine if Cdk5RAP1 may take part in regulating Cdk5 activity in neurodegenerative diseases. As a first ste...[ Read more ]

Cyclin-dependent kinase 5 (Cdk5), a proline-directed serine/threonine kinase, plays essential roles in CNS development. Its activation requires the association with its neuron-specific regulator, p35 or p39. Recent evidence reveals that deregulation of Cdk5 is linked to various neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, which are characterized by loss of selective neuronal populations. However, the molecular mechanisms implicated in the regulation of Cdk5 activity during neuronal apoptosis remain elusive. It has recently been shown that Cdk5RAP1, a protein that interacts with p35, is able to inhibit Cdk5/p35 kinase activity in vitro. It is thus of interest to examine if Cdk5RAP1 may take part in regulating Cdk5 activity in neurodegenerative diseases. As a first step to explore the potential functions of Cdk5RAP1 in the CNS, we examined its spatial and temporal expression profiles during development. We found that the expression of Cdk5RAP1 protein was developmentally regulated and was prominently expressed in the adult brain. Interestingly, subcellular fractionation and immunocytochemical studies revealed that Cdk5RAP1 protein was highly enriched in the mitochondrial fractions. Furthermore, overexpression of Cdk5RAP1 in neurons induced mitochondrial fission, a process involved in the induction of programmed cell death. Taken together, our findings suggest that Cdk5RAP1 might regulate Cdk5 activity in mitochondria during neuronal apoptosis.