CDK5: A Unique CDK and Its Multiple Roles in the Nervous System

Abstract

The cyclin-dependent kinase 5 (CDK5) is known as an exceptional component of the CDK family, due to its characteristic regulatory pathways and its atypical roles in comparison to the classical cyclins. Despite its functional uniqueness, CDK5 shares a great part of its structural similarity with other members of the cyclin-dependent kinase family. After its discovery 26 years ago, a progressive set of cellular functions has been associated with this protein kinase, ranging from neuronal migration, axonal guidance, and synaptic plasticity in diverse stages of brain development, including specific and complex cognitive functions. More than 30 substrates for CDK5 have been found in different cellular pathways. Together with its essential physiological roles, a major discovery was the finding twenty years ago that CDK5 participates in neurodegenerative diseases responsible for tau hyperphosphorylations, and, as a consequence, it becomes a neurotoxic factor. This review focuses on the wide roles of CDK5 in the central nervous system, its implications in neurodegeneration, and provides an integrative insight of its involvement in pain modulation, Alzheimer’s disease, and other contexts.

Keywords

Alzheimer’s disease CDK5 chemoreception nervous system tau

CDK5: THE UNIQUE KINASE

The cyclin dependent kinases (CDK) family is proline-directed serine/threonine kinases highly expressed in proliferating cells, mainly associated to regulatory processes of the cellular cycle [1, 2]. They are characterized by the need for other cyclins for their activation, being regulated through phosphorylation of specific T-loops by CDK-activating kinase (CAK), which promote its full activation, and being inhibited by membrane-associated tyrosine- and threonine specific cdc2-inhibitory kinase isoform 1 (Myt1) and Wee1 kinases [3, 4]. There are also multiple CDK inhibitor proteins that affect its kinase activity in the cellular cycle [5].

In 1992, CDK5 was described as a new proline protein kinase from bovine brain, which was similar to p34cdc2/cyclin dependent kinase 1 (CDK1) [6, 7]. Despite sharing a high homology with the rest of the proteins of the CDK family, CDK5 is an exception because it is activated classically by two non-cyclins proteins, p35 and p39, and also by cyclin I [8 –13] (Fig. 1). While CDK5 is ubiquitously expressed, p35 and p39 are predominantly present in neurons [14, 15]. p35 protein encompass the N-terminal region (p10) and C-terminal region (p25), and CDK5 can bind to p25 and become activated without the absence of p10 region [16 –18]. The p10 fragment includes the degradation signal of p35, which is rapidly cleaved by proteasomes [19]. p35 is phosphorylated by CDK5, which inhibits its own activity, through two specific sites of phosphorylation that are distinctively regulated during development, which allow control of the stability and spatial-temporal distribution of p35, and in turn, the activation of CDK5 [20, 21]. After a neurotoxic stimulus, which triggers a calcium increase, calpain cleaves p35 into p10 and p25 subunits [22]. As we discussed above, it has been observed that p35/CDK5 complex controls physiological roles during development, while p25/CDK5 binding is implicated majorly in pathological events. However, the deregulation of both complexes has cytotoxic consequences to the cells. The tendency of CDK5/p25 to be predominantly altered in non-physiological conditions is due to the fact that p25 is stable and does not contain the membrane anchoring signal present in p35, leading to its intracellular mislocation and the phosphorylation of multiple neurodegenerative targets [23, 24]. In a similar way, p39, an isoform of p35, shares more than 50% of its homology in genomic sequence, but has different patterns of expression. This is composed by p10 and p29 regions, resulting in the respective cleavage products after the calpain proteolytic action [12 , 26]. Cyclin I, an atypical cyclin that does not participate in regulating the cellular cycle, has been classified as a specific activator of CDK5 in postmitotic cells in primary cultures [13]. Similarly, an analog of Cyclin I, known as Cyclin I-like, is capable of activating the kinaseactivity of CDK5 in culture cells [27] (Fig. 1). In contrast, Cyclin D1, Cyclin E and Glutathione-S-transferase P1 (GSTP1) are inhibitors of CDK5 activity through their direct binding to the enzyme [28 –30]. Besides these main regulators, the latest evidence supports diverse ways of regulation at the transcriptional, post-transcriptional and post-translational levels of CDK5 [21], transforming it into a key target for treatment of specific pathologies.

Fig.1

Enzymatic activation of CDK5 in postmitotic cells. CDK5 become active after binding of p35, p39 and their respective cleaved fragments, p25 and p29. Cyclin I, Cyclin I-like, has been reported as specific CDK5 activators in primary culture. In addition, P35 is phosphorylated by CDK5, which inhibits its own activity. In contrast, Cyclin D1, Cyclin E, and Glutathione-S-transferase P1 (GSTP1) are CDK5 inhibitors.

Contrary to other members of CDKs family, CDK5 functions are predominantly in the central nervous system (CNS) and not in other tissues. It has a key role as a structural cytoskeleton regulator in the brain, modulating the activity of MAPs, and also in neuronal migration, axon guidance, synaptic plasticity, neuronal survival and associative learning and long-term behavioral changes [31]. It is highly expressed and differentially regulated in diverse stages of development throughout 30 specific substrates [31, 32]. In addition, pain modulation is one major topic that has been recently associated to CDK5, as will be detailed below [33]. On the other hand, CDK5 deregulation is implicated in neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease and amyotrophic lateral sclerosis (ALS) [34, 35] (Fig. 2). Despite its well characterized functions in the CNS, it is worth mentioning that CDK5, regardless of lacking a role in the cell cycle in proliferating cells, has the capacity to cause alterations in postmitotic neurons, activating abnormal effectors that lead to cell death [34]. In addition, CDK5 has been associated with cancer, epilepsy, schizophrenia and other important pathological contexts [36 –38], as will be explained later (Table 1). This review emphasizes the main physiological roles of CDK5 and its involvement in the pathogenesis of several diseases, through a refreshed view of recent literature.

Fig.2

CDK5 main physiological and pathological functions. Main physiological functions of CDK5 are associated to development of SNC, enhancing neuronal migration, axonal guidance, and synaptic plasticity, among others. Chemoreception modulation is also an important target of CDK5, regulating three different kinds of pain: nociceptive, inflammatory and neuropathic. In other hand, CDK5 deregulation affects diverse pathological events, enhancing neurodegenerative and neuropsychiatric disorders and cancer. Specific pathways and targets affected are described in Table 1. AD, Alzheimer’s disease; PD, Parkinson’s disease; ALS, amyotrophic lateral sclerosis; SZ, schizophrenia; EP, epilepsy; HD, Huntington’s disease; HCC, hepatocellular carcinoma; CA, cancer; CRC, colon rectal cancer.

Table 1

CDK5 pathological functions. CDK5 deregulation affect diverse pathological events, enhancing neurodegenerative and neuropsychiatric disorders and cancer. AD is the most prevalent neurodegenerative disease, and their main targets and process affected are indicated in table, related with CDK5 regulation. Similarly, schizophrenia and epilepsy are frequent neuropsychiatric disorders characterized by disruptions in diverse pathways that lead to alterations in CDK5 expression. In other context, although CDK5 roles are predominantly associated to CNS, it is also is altered in diverse pathological conditions related to cellular cancer lines

Pathology	Pathway or process affected	CDK5 expression (increase/decrease)	Complex involved (CDK5/p35-CDK5/p25) (CDK5/p39-CDK5/p29)	Target	Ref.
AD	Hyperphosphorylation of tau	CDK5 increased expression	CDK5/p39 - CDK5/p35- CDK5/p25	– Postmortem brain	[74 , 80]
				– Hippocampal primary culture
	Induction of NFT	CDK5 increased expression	CDK5/p39 - CDK5/p35- CDK5/p25	– Human cellular line SH-SY5Y	[78, 79]
				– Transfections and transductions
				– Hippocampal and cortical primary cultures
				– Transgenic AD mice
	Extracellular deposition of Aβ	CDK5 increased expression	CDK5/p25	– Human cellular line SH-SY5Y	[78 , 86]
				– Transient transfection
				– Hippocampal primary culture
	Phosphorylation AβPP	CDK5 increased expression	CDK5/p25	Cellular line HEK293	[15, 85]
	Leukotrienes metabolism	––	CDK5/p35- CDK5/p25	Hippocampal primary culture htau transgenic mice	[87]
SZ	Dopaminergic and glutamatergic	––	P35 reduction CDK5/p35- CDK5/p25	Postmortem brains	[38, 97]
		CDK5 increased expression	––	Dorsolateral prefrontal cortex in postmortem brains	[96]
EP	Neurotransmitter release through of P/Q-type voltage-activated calcium channels	CDK5 increased expression	CDK5/p35- CDK5/p39	Transgenic mice	[37 , 99–102]
HCC	Metastasis, higher differentiation, and vascular	CDK5 increased expression	–	Liver tissues	[111]
Breast cancer	Cancer progression, influence on epithelial-mesenchymal transition.	CDK5 increased expression	CDK5/p35	Breast cancer cell lines	[114]
CRC	Promote proliferation, tumor formation and invasion	CDK5 increased expression	CDK5/p35	Human CRC cell lines	[115]

AD, Alzheimer’s disease; NFT, neurofibrillary tangles; Aβ, amyloid-β; AβPP, amyloid-β protein precursor; SZ, schizophrenia; EP, epilepsy; HCC, hepatocellular carcinoma; CRC, colon rectal cancer.

CDK5: ITS ROLES IN CHEMORECEPTION AND PAIN

Among the different CDKs, CDK5 has been characterized by its roles in chemoreception pathways. The whole universe of pain signaling contemplates mainly three different kinds of pain: 1) nociceptive, 2) inflammatory, and 3) neuropathic. CDK5 displays molecular functions in the three types of pain,modulating the perception of pain in the subject. Briefly, we are going to summarize several of its implications at a molecular and functional level.

CDK5 and nociceptive pain

CDK5 mediates paramount molecular roles in pain signaling. Among its functional interactions, several pathways and molecular effectors are modulated or modulate this kinase. An example is proinflammatory effectors, such as the tumor necrosis factor-alpha (TNF-α), which activates p35 promoter activity. In the meantime, CDK5 upregulates p35 activity in a dose-dependent fashion. The previous effect was associated to the regulation of p35, since the extracellular signaling pathways-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), mitogen-activated protein kinase (MAPK), p38 and nuclear factor κβ (NF-κβ) are activated by TNF-α. In turn, all of them regulate p35, unveiling part of the mechanisms in pain signaling where CDK5 is implicated [39]. Moreover, in PC12 cells and dorsal root ganglia (DRG) neurons, the analgesic resveratrol blocks the TNF-α mediated increase in p35 promoter activity, reducing its expression and, as a consequence, CDK5 activity, unveiling part of its role in the treatment of pain [40, 41]. In addition, after treatment with HIV-1 Tat (a potent neurotoxic viral protein), the mechanisms involve the CDK system in the promotion of changes in the excitability of DRG, thus modulating pain signaling [41]. It seems that there are diverse and non-overlapping roles for CDK5 activators in the regulation of orofacial as well as peripheral nociception, with a crucial role for CDK5/p35 in pain signaling. Knockout experiments of p39 in mice do not affect peripheral nociception, and since there is lack of any algesic response to nociceptive stimuli in those mice, it contrasts with the hypoalgesic effects that result from the deletion of p35, and as a consequence, CDK5 activity [42]. In addition, CDK5 regulation of the transient receptor potential vanilloid 1 (TRPV1) membrane trafficking is a fundamental mechanism controlling the heat sensitivity of nociceptors [43]. CDK5 and p35 are expressed in murine odontoblast-enriched primary preparations of cells from the teeth. CDK5 is also functionally active in odontoblast-like MDPC-23 cells, by affecting the activity of the transforming growth factor-beta 1(TGF-β1). This has been shown to sensitize TRPV1 through CDK5 signaling in MDPC-23 cells, suggesting the direct involvement of odontoblasts and CDK5 in dental nociceptive pain transduction [44]. Nevertheless, mice overexpressing or lacking p35, showed an altered phenotype in response to noxious mechanical stimulation in the trigeminal area. Mice with increased CDK5 activity displayed aversive behavior to mechanical stimulation as indicated by a significant decrease in reward licking events and licking time. The number of reward licking/facial contact events is significantly decreased in these mice as the mechanical intensity increased. By contrast, mice deficient in CDK5 activity display mechanical hypoalgesia. CDK5 demonstrated to have a role in orofacial mechanical nociception. Modulation of CDK5 activity in primary sensory neurons makes it an attractive potential target for the development of novel analgesics that could be used to treat multiple orofacial pain conditions [45].

There are several proposals for controlling nociceptive pain, and many of them imply CDK5. Even so, many of these researches have led to novel hallmarks in CDK5 functional roles. For instance, acute administration of glial cell line-derived neurotrophic factor (GDNF) sensitizes nociceptors and produces mechanical hyperalgesia in the rat [46]. Inhibitors for all five signaling pathways are known to be activated by GDNF at GFRα1/Ret; PLCγ, CDK5, PI3K, MAPK/ERK and Src family kinases were evaluated. All of them attenuated GDNF hyperalgesia, which demonstrates a role of the non-peptidergic nociceptors in pain produced by the neurotrophin GDNF [46]. In a two-way context, considering nociception in cognitive function, postoperative cognitive dysfunction (POCD) was analyzed. POCD is associated with impairments in daily functioning and increased morbidity and mortality. On the other hand, uncontrolled pain often occurs postoperatively. After a surgical incision-induced nociception, the synaptic N-Methyl-D-aspartate (NMDA) receptor 2B level was reduced in the medial prefrontal cortex of mice, and the levels of TNF-α and CDK5 were increased in the cortex but not the hippocampus. These effects were attenuated with local anesthetics, including the CDK5 inhibitor roscovitine, which mitigated cognitive impairment and reduction of NMDA subunit. Briefly, these results suggested that the initial incision might lead to hippocampus-independent learning impairment, contributing to POCD by mechanisms involving CDK5 [47]. Still involving the NMDA receptors, CDK5 may contribute to remifentanil induced postoperative hyperalgesia by regulating the phosphorylation of NMDAR and mGluR5 in spinal dorsal horn. These findings provided experimental evidence for the further application of a CDK5 inhibitor in preventing remifentanil-induced hyperalgesia [48].

In a different context, there are reports of CDK5 activity which considers the role of the kinase in a cross talk between inflammation and nociceptive response. Briefly, it was published that CDK5 regulates mitogen-activated protein kinase1/2 (MEK1/2) activity through a negative feedback loop during the peripheral inflammatory response. Moreover, a differential nociceptive response after chronic morphine exposure in p35-/- and Tgp35 mice suggested that CDK5 activity is important for opioid tolerance. All these attributions and data indicate the important molecular roles for CDK5 in pain signaling and opioid tolerance, making it a potential target for analgesic drug development [49, 50].

CDK5 and inflammatory pain

It has been previously reported that during inflammatory pain, CDK5 participates in several ways. As we said before, the number of functional TRPV1 channels at the surface, especially at the peripheral terminals of primary sensory neurons, regulates heat sensitivity and increases surface localization of TRPV1 s contributing to heat hyperalgesia. CDK5 regulation of TRPV1 membrane trafficking is a fundamental mechanism controlling the heat sensitivity of nociceptors, and moderate inhibition of Thr-506 phosphorylation during inflammation might be helpful for the treatment of inflammatory thermal pain [43]. Furthermore, it was found that the position of T406 is critical for the function of TRPV1 by modulating ligand sensitivity, activation and desensitization kinetics as well as voltage-dependence. Based on high resolution structures of TRPV1, we discuss T406 being involved in the molecular transition pathway with its phosphorylation leading to a conformational change and influencing the gating of the receptor. CDK5-mediated phosphorylation of T406 can be regarded as an important molecular switch modulating TRPV1-related behavior and pain sensitivity [51]. Recently, CDK5 has also been reported to phosphorylate TRPV1 at threonine 407 (Thr-407) in humans (Thr-406 in rats), which enhances the function of TRPV1 channel and promotes thermal hyperalgesia in the complete Freund’s adjuvant (CFA)-induced inflammatory pain in rats [50]. It was demonstrated that CDK5 phosphorylates TRPV1 at Threonine 406 and promotes the surface localization of TRPV1, leading to inflammatory thermal hyperalgesia. These results demonstrate that CDK5-mediated phosphorylation of TRPV1 at Thr-406 increases the surface level and the function of TRPV1, while the TAT-T406 peptide can effectively attenuate thermal hyperalgesia [52]. Moreover, experiments performed in transgenic Crmp2ki/ki mice (CRMP2 S522A knock-in), focused on behavioral and proteomics analysis, showed no obvious differences in physical characteristics compared to wild-type mice, but they showed impaired emotional behavior, reduced sociality and low sensitivity to pain stimulation. Twenty pathways were detected in increased phosphopeptides and 16 pathways in decreased phosphopeptides, including “inflammatory mediators regulation of TRP channels” in crmp2ki/ki mice. This study suggested that the phosphorylation of CRMP2 at Ser522 by CDK5 is involved in the signaling pathways that may be related to neuropsychiatric and neurodegenerative diseases and pain [53]. Briefly, it has already been published that TNF-α increased p35 expression, causing CDK5-mediated TRPV1 phosphorylation followed by an increment in Ca^2 + influx in nociceptive neurons and increasing pain sensation. CDK5 activation mediated by p35 transfection in HEK293 cells or by TNF-α treatment in a primary culture of nociceptive neurons increased reactive oxygen species production. Moreover, this production is triggered by NOX1 and NOX2/NADPH oxidase complexes during inflammatory pain [54]. There is also an active cross-talk between TGF-β and CDK5 signaling pathways that affects pain. Understanding the cross-talks between inflammation and pain signaling is important for developing novel therapies to treat pain associated with chronic inflammatory diseases [55].

CFA-treated animals have been widely used as models for immune potentiation. In this context, several research efforts give us new insights on the subjacent mechanisms of inflammatory pain. For example, phosphorylation of δ-opioid receptor (DOR) at Thr-161 by CDK5 attenuates hypersensitivity and potentiates morphine tolerance in rats with CFA-induced inflammatory pain, while disruption of the phosphorylation of DOR at Thr-161 attenuates morphine tolerance [56]. In addition, it was reported that increased synaptophysin levels are involved in heat hyperalgesia mediated by CDK5 in spinal cord dorsal horns of CFA-treated rats, suggesting that inhibiting abnormal activation of CDK5-synaptophysin may present a novel target for diminishing inflammatory pain [57]. Furthermore, the BDNF-TrkB signaling pathway was involved in CFA-induced heat hyperalgesia mediated by CDK5. Roscovitine reversed the heat hyperalgesia induced by peripheral injection of CFA by blocking the Brain-derived neurotrophic factor BDNF/TrkB signaling pathway, suggesting that impairment of the close crosstalk between CDK5 and the BDNF/TrkB signaling cascade may be a potential target for anti-inflammatory pain therapies [58]. It was also found, that there is colocalization of p35 and the microglial marker OX-42andp– p38 in the same microglial cells and neurons of the spinal cord at day 1 after CFA injection; however, there is no colocalization of p35 and Glial fibrillary acidic protein, a marker of activated astrocytes. The thermal hyperalgesia induced by CFA is inhibited by intrathecal administration of roscovitine and by the p38 inhibitor SB203580. Furthermore, the expression of OX-42, p– p38, and TNF-α are remarkably increased from days 1 to 5 post-CFA injection and were significantly reversed by roscovitine between 1 and 3 days [59]. Moreover, there are studies in the human transient receptor potential ankyrin channel 1 (TRPA1), which is a polymodal sensor implicated in pain, inflammation and itching. Considering the potential involvement of the T/SP motifs as putative phosphorylation sites, it was shown that proline-directed Ser/Thr kinase CDK5 modulates the activity of TRPA1 and that T673 outside the AR-domain is its only possible target. This data suggests that the most strictly conserved N-terminal ARs define the energetics of the TRPA1 channel gate and contribute to chemical-, calcium-, and voltage-dependence [60]. Finally, p-CDK5S159 regulated by ERK pathway activity seems to be a critical mechanism involved in the activation of CDK5 in nociceptive spinal neurons, contributing to peripheral inflammatory pain hypersensitivity [61].

CDK5 and neuropathic pain

There are few roles for CDK5 in neuropathic pain. Among them, it has been reported that CDK5-dependent ERK activation underlies the estrogen-elicited facilitation on the repetitive stimulation-induced spinal reflex potentiation that is presumed to be involved in post inflammatory/neuropathic hyperalgesia and allodynia [62]. The CDK/ERK cascade, which is activated by ER-α and ER-β, may subsequently phosphorylate the NR2B subunit to develop NMDA-dependent post inflammatory hyperalgesia and allodynia to maintain the protective mechanisms of the body [62]. In the same receptor family, NR2A subunit has shown and expression inhibition by roscovitine, a known CDK5 inhibitor in DRG. Roscovitine also alleviated neuropathic pain, causing a decline in paw withdrawal mechanical threshold and paw withdrawal thermal latency. These results suggest that CDK5-NR2A pathway regulates neuropathic pain in DRG, and that intrathecal injection of roscovitine could alleviate neuropathic pain, giving insights into the analgesic effects of this compound by CDK5 modulation [63]. In other research, a significantly increased expression of CDK5 was observed in the dorsal horn of rats with chronic constriction injury, and intrathecal delivery of roscovitine significantly attenuated the mechanical allodynia in these rats. Phosphorylation of CREB and its occupancy in the CDK5 promoter region is also increased in the dorsal horn, leading to an increase of histone H4 acetylation in the CDK5 promoter region and the upregulated transcription of CDK5 [64].

Finally, following the classifications of pain presented above and the consideration of a different kind of pain, a window is opened to consider another context. It is known that the medial prefrontal cortex is implicated in processing sensory-discriminative and affective pain. Using a chronic inflammatory pain model, it has demonstrated a role for excitatory neurons in the prelimbic cortex (PL), a sub-region of the medial prefrontal cortex, in the regulation of pain sensation and anxiety-like behavior. The intrinsic excitability of contralateral PL excitatory neurons is decreased in chronic pain rats; knocking down CDK5 reverses this deactivation and alleviates behavioral impairments. Together, these findings provide novel insights into the role of PL excitatory neurons in the regulation of sensory and affective pain [65].

CDK5: ITS PATHOLOGICAL ROLE IN ALZHEIMER’S DISEASE

AD is a neurodegenerative disorder characterized by neuronal loss that leads to progressive and irreversible cognitive deterioration, which ultimately leads to dementia [66]. This disease is triggered mainly by the effects of both extracellular senile plaques (SP) and intracellular proteins, the neurofibrillary tangles (NFT). SP are constituted mainly by aggregates of amyloid-β (Aβ), whereas NFTs are composed mainly of hyperphosphorylated tau protein [67, 68]. The tau protein belongs to the family of microtubule-associated proteins (MAPs) and is considered a fundamental part of the neuronal cytoskeleton since it regulates the assembly oftubulin in microtubules and also binds these with other elements of the cytoskeleton, maintaining cell morphology [66]. These functions play a fundamental role in the growth of neurons during development and in axonal transport in mature neurons [69]. In agreement with the neuroimmunomodulation theory of AD [66], microglial activation by “damage signals” triggers proinflammatory mediators, which affects neuronal cells inducing a cascade of molecular signals that finally lead to an overactivation of proteins kinases, such as the glycogen synthase kinase GSK3β, CDK5, and others, responsible for tau hyperphosphorylation. In turn, tau posttranslational modifications unfold tau molecule favoring β-sheet conformations that are involved in tau-tau interactions in the pathway to formation of paired helical filaments (PHFs), and these in turn give rise to the NFTs [70]. Within the post-translational modifications that tau suffers, the protein phosphorylates in multiple sites, which leads tau to auto-aggregate, resulting in a loss of physiological functions and affecting cell integrity. Tau hyperphosphorylations are the product of an imbalance in the activity of kinases and phosphatases. In this context, the kinases involved in the modifications of tau and neuronal degeneration can be divided into two groups: 1) proline-directed kinases or proline-serine/threonine motifs (P-ST) and 2) kinases that phosphorylate motives other than P-ST, among which we can highlight MARK proteins, CaMPK II, PKA, and casein kinase II. In the first group, GSK3β and CDK5 stand out. CDK5 phosphorylate tau in residues S202, T205, S235 and S404 [71 –73].

If we turn to the physiological vein, CDK5 together with p35 have a direct participation in axonal growth and neuritogenic processes [74]. CDK5 has a fundamental role in the regulation of post-translational processes that lead to subcellular changes in the organization of the cytoskeleton. In support of this, there is evidence that neuritic dystrophy correlates with the expression of forms of clinical dementia and patients can tolerate certain levels of amyloidosis before presenting signs of cognitive impairment. The formation of SP is common both for normal aging and for patients with AD; tangles are rarely found without the presence of these plates, so it has been suggested that the deposition of Aβ precedes the formation of NFTs [70, 75]. However, it is possible that the formation of PHFs and SP produces, in a complementary way, the loss of the activity of affected neurons. An important discovery was the finding that the Aβ peptide induces alterations in the normal signaling pathway mediated by the CDK5 protein kinase system activated by p35 and p39 proteins, generating hyperphosphorylation of the tau protein [76, 77].

As mentioned above, CDK5 is particularly interesting because it can play a crucial role in the pathogenesis of AD and regulate the activity of other critical kinases, including GSK-3β. There is currently enough evidence to show that CDK5 induces extracellular deposition of Aβ in SP and intracellular accumulations of hyperphosphorylated tau in NFT [78]. The hyperphosphorylation of tau mediated by CDK5 inhibits the ability of tau to bind to microtubules, promoting the autoaggregation of this protein in PHFs and subsequently in NFTs, producing the disassembly of microtubules, which ultimately leads to synaptic loss and neuronal death. Studies carried out by Piedrahita et al. [79] observed that a decrease in the expression of CDK5 by means of gene silencing for this purpose through viral vectors loaded with interfering RNA of CDK5, managed to revert the hyperphosphorylation of tau in primary neuronal cultures and in the brain of wild mice C57BL/6. In turn, this decrease considerably reduced the amount of NFTs in the hippocampus of triple transgenic mice (3xTg-AD mice) [79].

Physiologically, CDK5 phosphorylates amino acid residues such as Ser202, Thr205, Ser235, and Ser404, which are hyperphosphorylated in the brain of patients with AD [80]. In turn, CDK5 can associate with p25, producing a significant increase in the kinase activity of this enzyme. Consequently, there is an increase in tau phosphorylation. Similarly, hyperphosphorylation of tau and neurofilaments in p25 transgenic mice has been discovered. The result of tau pathology induced by endogenous tau by p25 highlights the role of CDK5/p25 in the progression of neurofibrillary pathology in AD. However, the mechanism of p25 in tau hyperphosphorylation remains obscure because other studies support that the division of p35 to p25 only leads to greater activity of CDK5, not to hyperphosphorylation of tau [81]. It should be noted that the physiological activity of CDK5 and GSK-3β are of vital importance for the development of the central nervous system [82], which can phosphorylate Ser/Thr sites directed to the proline in tau and, in turn, induce the pathological phosphorylation of tau [83].

With respect to the activity of Aβ, the main component of SP, the protein undergoes proteolytic cuts by the β-secretase enzymes followed by γ-secretase in the transmembrane region releasing Aβ peptides [15]. In turn, CDK5 and Aβ are closely linked and affect each other. In this sense, CDK5 is intimately linked to the production of Aβ and its subsequent accumulation in the cell body of the neuron and also in the neurites. This fact induces neurotoxicity associated with a series of pathological events called amyloidogenic cascade, which triggers neuronal dysfunction, synaptic damage, hyperactivation of kinases, and ultimately leads to neuronal loss [84]. The pharmacological inhibition of CDK5 activity decreases the production of Aβ, which leads to a reduction of neuronal death induced by Aβ in transgenic mice that overexpress p25. CDK5 has also been implicated in the phosphorylation of amyloid-β protein precursor (AβPP), which makes it more prone to the formation of Aβ. The phosphorylation of AβPP in the amino acid residue Thr668 by Cdk5 can regulate its processing, increase the production of Aβ, and decrease the binding of AβPP to Fe65 (cytoplasmic adapter protein), whose function can inhibit the production of Aβ. It has been observed that the phosphorylation of AβPP mediated by CDK5 can affect the activity of GSK-3β, so that AβPP modulates the generation of Aβ [15]. Both in vitro andin vivo studies show that CDK5 can promote the levels of presenilin by direct phosphorylation of presenilin 1 in residue Thr354, which is necessary for the activity of γ-secretase and the catabolism of Aβ [85]. On the other hand, Aβ increases the intraneuronal calcium concentration, which leads to an activation of the calpains. It also causes the division of p35 to p25, and finally it produces deregulation of the CDK5 activity [86]. Recently, it has been shown that p35 and p25 exhibit a reduced pattern of expression and the improvement of spatial memory and learning after treatment with zileuton in a mouse model of tauopathies, which implies a new focus of a possible target for therapy through the leukotrienes pathways in AD [87].

CDK5 AND OTHER PATHOLOGICAL CONTEXTS

Schizophrenia and epilepsy

Another interesting role of CDK5 in the brain is related to two psychiatric and neurological disorders: schizophrenia and epilepsy. Schizophrenia is a severe and chronic psychiatric disorder [88] that includes multiple symptoms [88, 89]. Among these symptoms, cognitive impairment occurs in most patients with schizophrenia and is often present first, before any of the other symptoms. This disorder is thought to have its onset from a deregulation in the glutamatergic and dopaminergic signaling [90]. CDK5 activity is regulated by both of them and can in turn act as a feedback to regulate those signaling pathways [91 –93]. Moreover, the functions of candidate genes for schizophrenia are regulated by CDK5 activity [94, 95]. It has been demonstrated that the CDK5 activator p35, which regulates synaptic protein expression and cognition, is reduced in postmortem schizophrenia brains [38]. On the other hand, expression of CDK5 is increased on the dorsolateral prefrontal cortex in postmortem schizophrenia brains [96]. Reduction of both p35 and CDK5, along with p25, is observed when antipsychotic drugs are used [97]. Thus, the mechanism involving CDK5 in schizophrenia is closely related to their main activators.

Conversely, epilepsy is a neuronal disorder associated with abnormal electrical activity in the brain, which leads to an imbalance between excitation and inhibition [37]. CDK5 is a key player in regulating homoeostatic plasticity, which is crucial for stabilizing the activity of neurons and the neuronal circuits [37]. Homoeostatic plasticity may play a role in the prevention of epilepsy by balancing the excitatory and inhibitory neurotransmission [98]. Also, CDK5 is involved in the regulation of neurotransmitter release through the phosphorylation and downregulation of P/Q-type voltage-activated calcium channels [99]. P35 and p39 are involved in seizures during epilepsy [100 –102]. Opposite effects are observed, as in p35-/- mice, increased CDK5 activity, and seizure susceptibility [100], while the loss of p39 deregulates CDK5 activity and affects specific targets related to aberrant axonal growth in p39-/- mice [102]. Furthermore, contrary to what was observed in p35-/- mice, p39-/- mice present an ameliorated response to pharmacologically induced seizures [102].

When conventional anti-epileptic drugs cannot control seizures, the condition is stated as drug-resistant epilepsy (DRE), which affects 25% of epileptic patients [103]. This affects the patient’s quality of life due to the severity of their seizures [103]. In that context, in the anterior temporal neocortex of DRE patients CDK5 is higher when compared to controls [104]. The latter could alter dopaminergic homoeostasis under conditions of increased levels of glutamate, causing excitotoxic damage. Activation of the glutamatergic signaling, through the NMDA and AMPA receptors, leads to an increase in intracellular Ca^2 + concentration. Moreover, an overexcitatory feedback circuit and spontaneous seizures in p352/2 mice involves the AMPA and NMDA receptors [105].

CDK5 in pathologically proliferating cells

CDK5’s function in cells, other than neurons, includes the induction of cell motility, apoptosis and cell cycle progression. It is also involved with functions of the immune system, lymphatic system, vascularization and insulin secretion. Its role in apoptosis and cell cycle is crucial in its involvement in cancer.

Elevated levels of CDK5 were detected in several mouse and human malignant tumors [106 –109] with potent effects on cell proliferation, angiogenesis, and the immune system. CDK5 enhances pRb phosphorylation and, thereby, cell-cycle progression [106]. Also, it phosphorylates by CK1, which regulates cell cycle, DNA repair, and apoptosis[110].

In human hepatocellular carcinoma (HCC), it was demonstrated that CDK5 expression levels were increased when compared to the normal liver, the noncancerous adjacent liver, and the cirrhotic liver [111]. This upregulation was associated with metastasis, higher differentiation, and vascular invasion [111]. Thus, CDK5 is essential for the initiation and progression of HCC. In prostate cancer, CDK5 catalyzes the phosphorylation of androgen receptor at Ser-81 to stabilize and to accumulate androgen receptor proteins and, subsequently, to be activated to regulate the growth of prostate cancer cells [112]. In pancreatic cancer, CDK5 is amplified, overexpressed and activated by mutant K-Ras; inhibition of CDK5 blocks cancer formation and progression through the suppression of Ras-Ral signaling [113]. In breast cancer, CDK5 and p35 were highly expressed in a variety of breast cancer cell lines and breast cancer tissues [114]. Also, CDK5 was abnormally overexpressed in clinical human breast cancer samples and was significantly correlated with several poor prognostic parameters of breast cancer [114]. Breast cancer progression is closely related to the epithelial-mesenchymal transition (EMT) and CDK5 participated in the TGF-b1 induced EMT in these cells [114]. Moreover, TGF-b1 factor upregulates CDK5 and p35 in MCF10A cells [114]. Thus, this CDK5-FAK pathway, which is downstream of TGF-b1 signaling, is critical for EMT and motility in breast cancer cells. In colon rectal cancer, CDK5 promotes proliferation, tumor formation and invasiveness, at least in part, through the modulation of the ERK5– AP-1 signaling axis [115], acting as a tumor promoter.

The latter describes only a few examples on how CDK5 is involved in malignant tumors. It is interesting how CDK5 could be a novel target for the treatment of malignant tumors [116], a complex problem since CDK5 plays critical physiological roles in many activities of the cell.

CONCLUSIONS

CKD5 is a unique enzyme because it is involved in a variety of physiological roles and in developmental processes of the central nervous system. Modulation of chemoreception processes is an important activity of CDK5, regulating three different kinds of pain: the nociceptive, inflammatory and neuropathic pain. On the other hand, the relevance of the CDK5 system is attested by the fact that its deregulation is directly involved in diverse pathological events, enhancing neurodegenerative and neuropsychiatric disorders and cancer. However, a main issue was the discovery that a deregulation of this protein kinase is directly involved in tau hyperphosphorylations. This research was carried out in our laboratory [72 , 74–77] as well as in Tsai’s laboratory [80] in 1999. It has been demonstrated that CDK5 participates in neurodegenerative diseases, being responsible for tau modifications, the critical event that triggers its self-aggregation responsible for generation of neurofibrillary tangles, subsequently resulting in neurotoxic actions in the brain. Thus, CDK5 is intimately involved in the pathophysiology of tau protein and in the formation of NFTs by hyperphosphorylation of multiple amino acid residues of this protein. In turn, the CDK5/p25 complex mediates AβPP metabolism and causes pathological phosphorylation of AβPP, which influences the formation of Aβ. Aβ and CDK5 form a positive feedback loop that triggers a series of AD pathological events, since Aβ can also contribute to the abnormal CDK5activity.

Footnotes

ACKNOWLEDGMENTS

This research and review preparation has been supported by INNOVA CORFO projects, the ICC Fund and The Ricardo Benjamin Maccioni Foundation. We thank Constanza Maccioni for her helpful discussions and support in the logistic aspects.

Authors’ disclosures available online ().

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