CDK5 is a special member of the CDK family. This kinase does not participate in the regulation of the cell cycle. It mainly displays its activity in neurons after mitosis, and has no kinase activity itself. It has been reported in the literature that most of CDK5 exists as a monomer, and it has kinase activity only after binding to its specific activating factors P35 and P39. CDK5 regulates function by phosphorylating a variety of protein substrates, and is thought to be involved in neuronal cell cycle reentry after mitosis. Some scholars have discovered that DNA damage drugs can induce neurons to enter the cell cycle, and the phenomenon that neurons die is called cell cycle reentry. More specifically, when neurons enter the S phase, they will cause death. Therefore, in order to maintain the survival of neurons in a physiological state, the mechanism leading to the reentry of the neuronal cell cycle must be in an inhibited state.

Figure 1. Protein structure of CDK5.

Source

CDK5 was first isolated and screened for human cell cycle regulatory kinase (cdc2) -related kinases from bovine brain tissue. It has 58% and 62% homology with cdc2 and cdk2, respectively. CDK5 contains all conserved protein kinase domains and contains domains common to members of the cdk family in region III. CDK5 protein is composed of 292 amino acid residues with a relative molecular mass of 33x103. The amino acid sequence homology between different species (human, cattle, rat, mouse) reaches 99%, indicating that the protein Highly conservative. Ckd5 is a multifunctional kinase whose main function is to participate in nerve cell migration, axon guidance, synapse generation and transmission. Recent studies have found that CDK5 is expressed in a variety of tissues, and it can play a variety of biological functions by phosphorylating different regulatory substrates.

Functions

CDK5 can phosphorylate parkin protein in vivo and in vitro, which affects the activity of parkin protein ubiquitin-ligase, resulting in a decrease in autoubiquitination activity in vivo. In addition, foreign reports have shown that CDK5 and tyrosine kinase I can reduce the hydrolysis of parkin protein and cause its accumulation in the body; CDK5 phosphorylation of α-synuclein protein can also cause its accumulation in the body. In the brain of Parkinson's patients, CDK5 and P35 can be found in the body of Lewy's small body, further confirming that CDK5 is involved in the formation of α-synuclein. In addition, CDK5 has a great effect on the oxidative capacity of dopamine neurons. Overexpression of CDK5-activated MPK+ will reduce the peroxidase activity of Prx2, thereby reducing the ability of intracellular oxides to clear, and will eventually lead to neuronal senescence. CDK5 does not participate in the cell cycle operation and cell division in the development of the nervous system, but plays many important physiological and pathological functions in post-mitotic neurons. CDK5 regulates various functions by acidifying a variety of protein substrates, and is considered to be involved in the re-entry of the neuronal cell cycle after mitosis, and is involved in the formation of Parkinson's disease.

CDK5 and Parkinson's disease

From the perspective of neuropathology, Parkinson's disease is a selective dopaminergic neuron decay, especially in the substantia nigra dense area. The loss of neurons and the formation of intracellular Lewis body polymers are two pathological main features. Although the precise mechanism of dopaminergic neuron apoptosis has not yet been discovered, recent studies have shown that CDK5 is involved in this process. This kinase has abnormal activity in patients and animal models of Parkinson's disease, especially in the regulation of MPTP neurotoxins. This mechanism may be related to the excitotoxicity of glutamic acid. The production of MPTP increases the activity of glutamic acid, and the balance of calcium and calpain is broken. Studies have found that using CDK5 inhibitors or blocking P35 activating factors, Parkinson's disease shows a significant increase in both cellular and overall behavioral levels of animals.

References:

1. Meyerson M; et al. A family of human cdc2-related protein kinases. The EMBO Journal. 1992,11 (8): 2909–17.
2. Patrick GN; et al. Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature. 1999, 402 (6762): 615–22.