Sci. Aging Knowl. Environ., 17 December 2003
Vol. 2003, Issue 50, p. pe36
[DOI: 10.1126/sageke.2003.50.pe36]

PERSPECTIVES

Cyclin-Dependent Kinase 5--A Neuronal Killer?

Qing Guo

The author is in the Department of Physiology, University of Oklahoma Health Sciences Center, College of Medicine, Oklahoma City, OK 73104, USA. E-mail: qing-guo{at}ouhsc.edu

http://sageke.sciencemag.org/cgi/content/full/2003/50/pe36

Key Words: cyclin-dependent kinase • Cdk5 • amyloid • tau • p35 • p25 • neurodegenerative disease • neurofibrillary tangle

Neuronal loss resulting from apoptotic or necrotic neuronal cell death is a common feature of many neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS ), and stroke (1). Despite extensive studies, the precise molecular mechanisms that underlie neuronal cell death in neurodegenerative disease remain largely unknown. Recent studies suggest that aberrant activation of cyclin-dependent kinase 5 (Cdk5) (a serine-threonine kinase that has a number of functions in the mammalian brain) by a truncated version (p25) of the Cdk5 regulatory subunit p35 may be a key event in the process of neurodegeneration (2-8).

The two pathologic hallmarks of AD are amyloid plaques and neurofibrillary tangles (NFTs) (see "Detangling Alzheimer's Disease"). Amyloid plaques are composed primarily of aggregated amyloid {beta} peptide (A{beta}), which is derived from beta amyloid precursor protein (APP), whereas NFTs result from hyperphosphorylation of the protein tau. Precisely how these pathological features are linked to the neuronal cell death seen in AD is unknown and is a matter of continuing controversy. Several lines of genetic and biochemical evidence suggest that aggregated A{beta} is neurotoxic and may be responsible for the massive neuronal loss in brain regions associated with learning and memory, such as the hippocampus and the cerebral cortex. The prevailing amyloid hypothesis of AD proposes that aberrant increased production and aggregation of A{beta} are an early and primary cause of neuronal loss in AD. Abnormal hyperphosphorylation of tau causes microtubules to fall apart. For the neuron, this lack of microtubules means a lack of normal axonal transport. Thus, hyperphosphorylation of tau might be a primary cause of neurodegeneration. The relationship between A{beta} aggregation and the formation of NFTs is not clear, although recent studies indicate that Cdk5, which phosphorylates tau, may provide the long-sought link between amyloid plaque formation and hyperphosphorylation of tau (2, 4, 5, 7-10).

Cdk5 is a 33-kD proline-directed protein kinase that phosphorylates serine and threonine residues and is ubiquitously expressed in mammalian tissues. The Cdk5 monomer has only negligible enzymatic activity; the kinase is activated by neuron-specific p35, by a proteolytic product of p35 called p25, and by a protein homologous to p35, p39 (11-13). Under normal physiological conditions, Cdk5 and p35 are integral players in the proper development of the mammalian central nervous system. p35 is a 35-kD protein identified as the first regulatory subunit of Cdk5. In brain lysates, it physically interacts with Cdk5, and this direct binding activates Cdk5. Although Cdk5 is expressed in most tissues, its activity is largely restricted to neurons, because p35, p25, and p39 are expressed mainly in neurons. Proteins that have been shown to be phosphorylated by Cdk5 include cytoskeletal elements, cell adhesion molecules, proteins involved in membrane cycling and axonal transport, and signal transduction kinases involved in cytoskeletal regulation or neuronal migration (2-4, 9). Because triple transgenic mice that overexpress human p35, Cdk5, and tau do not display an increase in tau phosphorylation despite significant increases in Cdk5 activity, p35/Cdk5 almost certainly does not efficiently phosphorylate tau (14). p25 also is fully capable of activating Cdk5; however, this 25-kD proteolytic fragment of p35 displays a different subcellular localization and, because of distinct biochemical properties, different substrate specificities than does p35. p25 is more stable than p35 and is more heavily concentrated in perinuclear regions. Thus, p25 can cause aberrant activation and redistribution of Cdk5, and consequent phosphorylation of "pathological" substrates. For example, in vitro recombinant p25/Cdk5 phosphorylates tau with higher efficiency than does p35/Cdk5 (15). The physiologic role of p25 is unknown. Although tau is a phosphoprotein normally located in the axons of neurons, in the brains of patients with AD, hyperphosphorylated tau is found in cell bodies and dendrites, a so-called somatodendritic distribution. The distribution of p25 appears to match that of hyperphosphorylated tau.

Tau and neurofilament H (NFH) are cytoskeletal proteins that often are hyperphosphorylated in degenerating neurons, and both proteins have been implicated in AD, PD, and ALS. In primary cultures of neurons, p25 is produced by cleavage of p35 between residues 98 and 99 in response to neurotoxic insults (including A{beta} treatment). This cleavage site also is used in vivo. One enzyme responsible for cleavage of p35 is calpain, a calcium-activated protease that has been shown to be involved in neuronal cell death (16). The amounts of calpain have been shown to be increased in the brains of patients with AD, and disturbed calcium homoeostasis is a common feature and an early event in many neurodegenerative diseases (16-18). Overexpression of p25 in cultured cortical neurons results in disruption of the cytoskeleton, hyperphosphorylation of tau, and apoptotic cell death (16, 19, 20). These results, together with the observation that pharmacological inhibition of Cdk5 attenuates A{beta} neurotoxicity, indicate that aberrant Cdk5 activation by p25 is neurotoxic and is involved in the development of neurofibrillary pathology. It seems possible that calcium-induced conversion of p35 to p25 and subsequent Cdk5 overactivation and redistribution are critical upstream events in the cascades that eventually lead to neurodegeneration. The accumulation of p25 (and hence the abnormal increase in Cdk5 activity) is implicated in several neurodegenerative diseases, including AD and animal models of ALS and Niemann Pick type C disease (16, 20-23).

Two recent publications appear to provide direct in vivo evidence that aberrantly activated Cdk5 functions in neurodegeneration (5, 24). In one paper, J. C. Cruz and colleagues used the tetracycline-inducible transcriptional activator system to generate transgenic mice that overexpress the human p25 gene under the control of the CamKII (calcium-calmodulin kinase II) promoter, which drives high transgene expression in the forebrain (24). These mice expressed elevated p25/Cdk5 activity without affecting endogenous p35/Cdk5 activity. p25 displayed a somatodendritic staining pattern in neurons of the cerebral cortex and the hippocampus. Unlike p35, p25 did not localize to axonal fiber tracts in the forebrain. In these mice, age-dependent neuronal loss, which was accompanied by extensive astrogliosis (an increase in the number of astrocytes caused by the destruction of neighboring neurons) and activation of the apoptosis-inducing enzyme caspase-3, occurred in a pattern that correlated with the distribution of p25 expression in transgenic mice. After 12 weeks of p25 induction, about 40% of neurons were lost from the cortex and hippocampus, suggesting that the apoptotic machinery is activated in vivo by p25.

Cruz et al. also showed that deregulated Cdk5 activity leads to the hyperphosphorylation and accumulation of aggregated tau in vivo. These events coincide with the onset of neuronal loss in the cerebral cortex and the hippocampus and precede the formation of NFT-like structures that ultimately culminate in neurofibrillary pathology. Although phosphorylation of tau and other pathological Cdk5 substrates such as neurofilaments and APP is up-regulated, the phosphorylation of known physiological Cdk5 substrates such as Nudel, mDab1, and PSD95 in vivo was not increased in these p25 transgenic mice, suggesting that in addition to overactivating and redistributing Cdk5, p25 might redirect Cdk5 activity to alternative substrates--ones involved in neurodegeneration. These findings are especially important, because the neurodegeneration phenotype and tau hyperphosphorylation in these mice are in sharp contrast to previously published data on p25 transgenic mice, in which expression of human p25 was under the control of the NSE, PDGF, or CMV promoters (25-27). In these p25 transgenic animals, no conclusive tau hyperphosphorylation or neuronal death was observed in the cortex or hippocampus. The generation of inducible p25 transgenic mouse lines that overexpress p25 in the postnatal forebrain therefore represents a new mouse model in which tauopathy is derived from endogenous tau and increased kinase activity. Two major factors may account for the expression of this phenotype: (i) use of a CamKII promoter to drive high p25 expression in the forebrain, and (ii) elimination of developmental compensation by using an inducible expression system. These findings provide important in vivo evidence that deregulation of Cdk5 by p25 plays a causative role in neurodegeneration and the development of neurofibrillary pathology. Because A{beta} has been shown to increase the conversion of p35 to p25 in primary neurons, aberrant activation of Cdk5 by p25 may represent a pathway that connects A{beta} toxicity to tau hyperphosphorylation in AD.

Calcium has previously been implicated in neurodegenerative disease. For example, disruption of intracellular calcium homeostasis has been linked to the pathogenic mechanisms that underlie the pro-apoptotic actions of presenilin-1 mutations (17). Increased intracellular calcium levels also have been shown to induce aberrant expression of another pro-apoptotic protein, prostate apoptosis response-4 (Par-4) (18, 28) Normally, Par-4 is found enriched in nerve terminals, where it might participate in inhibiting neurite outgrowth. But Par-4 concentrations are significantly increased in vulnerable regions of the AD brain, and in vitro and in vivo studies have documented that Par-4 promotes neuronal cell death after insults relevant to the pathogenesis of AD (such as withdrawal of trophic support from culture media or exposure to A{beta} 1-42) (29). Increased concentration of Par-4 also has been implicated in the pathogenesis of PD (see Andersen Review) and ALS (30, 31). Overexpression of Par-4 has been shown to alter APP processing, resulting in an increased production of the amyloidogenic fragment A{beta} 1-42 (32). Because calcium also plays an important role in activating calpains, which convert p35 to p25 and thereby lead to an aberrant increase of Cdk5 activity, these data suggest that disruption of intracellular calcium concentrations might play a central role in activating multiple pathways that lead to aberrant A{beta} production and neuronal cell death (Fig. 1).



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Fig. 1. Proposed central role of disrupted intracellular homeostasis in activating cellular pathways that lead to an aberrant stimulation of Cdk5 activity, an increase in the amounts of Par-4 protein and neurotoxic A{beta} 1-42 peptide, and hyperphosphorylation of tau, all of which lead to neuronal cell death in AD. Presenilin mutations and apoptotic insults [such as the withdrawal of trophic factors (TFW) or glucose from culture media] may disrupt intracellular calcium homeostasis, resulting in increased intracellular calcium concentrations ([Ca2+]i). The high concentrations of calcium might then activate calcium-dependent calpains, which in turn increase the conversion of p35 to p25. The abnormally high concentration of p25 leads to overactivation of Cdk5 and phosphorylation of pathological substrates such as tau. Whether overactivation and redistribution of Cdk5 directly or indirectly activate caspases needs to be elucidated. An abnormal increase in the concentration of intracellular calcium also induces expression of Par-4, which might directly or indirectly increase production of the amyloidogenic A{beta} 1-42 and induce mitochondrial dysfunction and caspase activation. A{beta} 1-42 also may increase the amount of cleavage of p35 to p25. Neurotoxic A{beta} 1-42 aggregates, tau hyperphosphorylation, and the activation of caspases eventually lead to cell death.

 
In an article published recently in Proceedings of the National Academy of Sciences of the United States of America, Patrice D. Smith and colleagues provided additional in vivo evidence of a critical role for aberrant Cdk5 activity in neurodegeneration, this time in an animal model of PD (5). PD is a progressive neurodegenerative disorder in which motor problems (tremor, rigidity, bradykinesia, and postural instability) are pathologically associated with the formation of Lewy bodies and the eventual loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). Because dopaminergic neurons normally provide inhibitory innervations to the striatum, loss of dopamine in the striatum results in an imbalance of excitatory and inhibitory regulation of motor activity in PD. Cdk5 has previously been shown to modulate dopamine signaling in dopaminergic neurons. For example, deregulation of Cdk5 has been documented in an animal model of ALS that carries a mutation in a superoxide dismutase 1 gene (22). Cdk5 reportedly is elevated in dopamine neurons of human postmortem PD brains, and expression of Cdk5 occurs in neonatal rat dopamine neurons undergoing programmed cell death in vivo. Smith and colleagues reported that in the mouse MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of PD, flavopiridol, which inhibits Cdk function, attenuated MPTP-induced loss of dopaminergic neuronal cell bodies in the SNc after chronic MPTP treatment and MPTP-induced hypolocomotion, thus indicating that Cdk family members play a required role in nigral degeneration. The investigators observed elevated amounts of p25 and phosphorylation activity of Cdk5 in the SNc of MPTP-treated animals. Expression of a dominant negative mutant form of Cdk5 protected against death of SNc dopaminergic neurons. These results indicate that an increase in Cdk5 activity, induced by p25, plays the major role in MPTP-induced loss of dopaminergic neurons.

Consistent with this observation, the same group previously demonstrated that calpains are activated and are required for death in the chronic MPTP paradigm of PD (33). However, neuroprotection conferred by inhibition of Cdk5 activity did not lead to improved striatal dopamine levels or altered dopamine turnover, indicating that striatal dopamine fibers remained functionally impaired. The observed improvement in locomotor activity without normalized dopamine levels in the striatum indicates that flavopiridol-mediated protection of dopamine neuron cell bodies might indirectly modulate postsynaptic striatal function. Indeed, MPTP-induced expression of {delta} FosB (an immediate-early gene) in striatal dopamine receptor neurons was attenuated significantly by flavopiridol treatment. Expression of an immediate-early gene is a good indicator of postsynaptic striatal neuron activity, and thus this result supports the hypothesis that inhibition of Cdk activity improves the MPTP-induced loss of locomotion in these mice by inhibiting postsynaptic changes in the striatum. Expression of a dominant negative mutant of Cdk2 also gave some protection against loss of dopaminergic neurons in MPTP-treated mice. Thus, Cdk2 might play a role in the neurodegenerative process initiated by MPTP, albeit a lesser role than Cdk5.

The insight derived from these in vivo studies is especially important, because it implicates deregulation of Cdk5 by p25 in neurodegeneration in animal models of neurodegenerative diseases. Indeed, studies on Cdk5 have generated a mounting interest among many neuroscientists, because Cdk5 seems to provide a long-sought link between amyloid plaques and NFTs in AD. However, many questions remain. The first and perhaps most important is the difficulty of reliably replicating the results of animal studies in humans. Despite experimental data pointing to the contrary, a recent study by Tandon and colleagues of 25 cases of sporadic and familial AD, as well as cases of other neurological diseases that exhibit NFTs, such as Down syndrome, Pick's disease, corticobasal degeneration, and progressive supranuclear palsy, found no evidence of elevation in p25 concentrations or the p25/p35 ratio in brains from patients with AD or other tauopathies, as compared with brains from neurologically normal controls. The conclusion from these data would be that cleavage of p35 to p25 and aberrant Cdk5 activity are unlikely to contribute significantly to AD pathology (34). In fact, p25 immunoreactivity tended to be lower in the AD brains when normalized to the concentration of glyceraldehyde-3-phosphate dehydrogenase. With three different polyclonal antisera to p35, no correlation was found between the amounts of p25 and the presence of NFTs. The amount of detergent-extractable Cdk5 was reportedly reduced in sporadic AD brains as compared to control and familial AD brains, whereas insoluble Cdk5 immunoreactivity was preserved. The functional implications of this change are unclear, because the amount of neither soluble nor insoluble Cdk5 was found to correlate with the amount of phosphorylated tau (34). These results were in marked contrast to those reported by Tsai and colleagues, who initially reported a 20- to 40-fold increase of p25 in AD brains (21).

In addition, studies in TgCRND8 transgenic mice, which express a doubly mutated form of APP and show A{beta} plaques in the brain and severe cognitive deficits at 3 months of age, found no concomitant change in p35 or p25 concentrations despite the significant age-related rise in amounts of A{beta} peptide (34). This result contrasts with the observation that A{beta} peptide treatment of cultured primary mouse neurons promotes calpain-mediated proteolysis of p35 to p25. Another concern regarding a causative role for deregulation of Cdk5 by p25 in neurodegeneration is the lack of a direct link between p25 and the apoptotic machinery. Taken together, these results illustrate that the precise mechanism(s) by which Cdk5 modulates downstream cell death effectors still need to be carefully elucidated.


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Citation: Q. Guo, Cyclin-Dependent Kinase 5--A Neuronal Killer? Sci. Aging Knowl. Environ. 2003 (50), pe36 (2003).




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