Literature: A-K ; L-Z ; subject area
Compiled by: Julian Thorpe
Cyclin-Dependent Kinase 5 (Cdk5)
|
Please Note: Due to time constraints, the text part of this page has not been updated for some time. However, references are added reasonably frequently. |
Cdk5 (
see Maccioni et al., 2001; Smith et al., 2001) is abundant
in brain tissue and has been shown to associate with
tau
(and neurofilament
and tubulin
proteins; Veeranna et al., 2000).
 | With its neuron-specific activator p35, Cdk5 is required for neuritic outgrowth, cortical lamination and synaptogenesis in cultured rat brain neurons (Tokuoka et al., 2000). |
| In AD, p25, a proteolytic cleavage product of p35, accumulates in the brain and promotes activation and mislocalization of cdk5 (Patrick et al., 1999). The p25/cdk5 kinase then hyperphosphorylates tau , leading to cytoskeletal disruption and the (apoptotic) death of primary neurons (summarised from Lee et al., 2000). |
| See the recent minireview by Maccioni et
al. (2001)
for an overview of involvement in neurogenesis and AD.
|
Some Research Results:
| Lew et al. (1994) purified a novel Cdc2-like kinase from bovine brain which phosphorylates neurofilament proteins and tau .It was a heterodimer of Cdk5 and a novel regulatory subunit, p25. The latter could activate Cdk5 in vitro and is expressed only in brain. p25 was shown to be a truncated form of p35, which is the predominant form in crude brain extract. |
| Lew and Wang (1995)reported that neurofilament proteins and the neuron-specific microtubule-associated protein tau are phosphorylated in vivo at sites conforming to the phosphorylation consensus motif of the cell-cycle-control protein kinase, p34cdc2-cyclin. Abnormalities in the phosphorylation of these proteins are associated with neurodegenerative disorders, such as amylotrophic lateral sclerosis and Alzheimer's disease. A cdc2-like kinase composed of cyclin-dependent kinase 5 (cdk5) and a brain-specific regulatory subunit is proposed to be responsible for the cdc2-like phosphorylation of these neuronal proteins. |
| Matsushita et al. (1995) investigated the distribution and developmental changes of cdk5 in the cerebellum. It was consistently expressed at all developing stages. In the early neonatal stage, Cdk5 was strongly expressed in the cell bodies while upon neuronal maturation it moved to the axon. They suggested that cdk5 may play an important role in neuronal maturation. |
| Imahori and Uchida (1997) have shown that tau protein kinase II (TPKII; consisting of a novel 23 kDa protein activator and cdk5 ) and TPKI (GSK-3 beta) could account for most of the major phosphorylation sites of fetal and PHF-tau . TPKII (and GSK-3 beta) were associated with NFT s in vivo and also were suggested to be important in the formation of neural networks in the neonatal brain. |
| Lee et al. (1999) examined neuronal Cdc2-like kinase activity in prefrontal and cerebellar cortex from AD and control subjects (corrected either for Cdk5 level or neuronal loss). The ratio of neuronal Cdc2-like kinase activity in prefrontal versus cerebellar cortex was then compared. The ratios were higher in AD than the controls, a finding consistent with a role for neuronal Cdc2-like kinase in the pathogenesis of NFT in AD. |
| Alvarez et al. (1999) used cultured rat hippocampal cells to study the tau protein kinase II system (TPK II; involving cdk5 and p35). They showed that fibrillary beta-amyloid increased cdk5 activity, while a cdk5 inhibitor and an (cdk5) antisense probe protected the cells from beta- amyloid-induced neurotoxic damage. They therefore concluded that cdk5 plays a major role in the molecular path leading to the neurodegenerative process. |
| With regard to kinase inhibitors, Meijer and co-workers ( Gray et al., 1999; Borgne and Meijer, 1999) anticipate the discovery of novel selective and powerful (kinase) inhibitors which may be of therapeutic value in AD. |
| Patrick et al. (1999) have shown that p25 (a truncated form of p35) accumulates in neurons in AD brains and this correlates with an increase in Cdk5 kinase activity. The p25/Cdk5 complex hyperphosphorylates tau, and expression in cultured primary neurons induces cytoskeletal disruption, morphological degeneration and apoptosis. Evans et al. (2000) have subsequently shown that phosphorylation of serine residues 396 and 404 (by tau protein kinase II [Cdk5]) is primarily responsible for the mediation of tau's inability to polymerise tubulin . |
| Associated with complexes of NF proteins , tubulins and tau (Veeranna et al., 2000). |
| Ahlijanian et al. (2000) used transgenic mice (overexpressing human p25, which activates cdK5) to show hyperphosphorylation of tau and neurofilaments by cdk5. This latter was accompanied by cytoskeletal disruption. |
| Tokuoka et al. (2000) showed that NF-H phosphorylation (in cultured rat brain neurons) was stimulated by brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3) and correlated with synapse formation. The BDNF-stimulated phosphorylation (and thus synapse formation) was mediated, at least in part, through activation of cdk5. |
| Lee et al. (2000) showed that beta-amyloid, excitotoxins, hypoxic stress and calcium influx induce the production of p25 (from p35) in cultured primary cortical neurons. Calpain (a calcium-dependent cysteine protease) was found to cleave p35 to release a product corresponding precisely to p25. Inhibition of cdk5 or calpain reduced cell death in beta-amyloid treated neurons. |
| Leost et al. (2000) report that paullones are potent
inhibitors of neuronal cdk5/p25 (and GSK-3 beta). The authors suggest that these compounds could be useful tools
for the study and possible treatment of neurodegenerative disorders. |
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