Between the intervene 2000 years were dominated by supernatural views and this is enforced that epilepsy is nothing but Christ casting out a devil from a person. Throughout this time, people with epilepsy were viewed with fear, suspicion and misunderstanding sometimes affected person can be treated as outcast and punished but we now know that it is nothing but imbalance in excitation and inhibition of neurons is an indication of epilepsy generation ( A disorder in which nerve cell activity in brain is disturbed causing seizures). And in this blog, we mainly focus on the CDK5 and its role in epilepsy. Form past years scientist have many papers associated between abnormal synaptic transmission and epileptogenesis, and yet we not able to decipher the molecular mechanism between the seizures in patients with epilepsy, specially drug resistance epilepsy (DRE), is still unclear. Drug resistance epilepsy prove to not affected by antiepileptic drug (AED) to control seizure completely, so this patient shows poor social life and high risk of mortality. 

The epileptoleptic patient undergo various tests like

  • Electroencephalography (EEG)
  • Magnetic resonance imaging (MRI)
  • Positron emission tomography (PET)
  • Single photon emission computed tomography (SPECT)

This technique helps scientist or doctors to find out the potential surgical lesion or localize cerebral dysfunction by finding out the disturbances in an individual’s metabolism. Recent technique magnetoencephalography (MEG) very powerful to localize the affected injured and non-injured epilepsy surgery patients. There are some patients who continue to have seizures even after surgery and they are given other antiepileptic drug (AED) or vagus nerve stimulation or cortical stimulations or ketogenic diets to control the seizures. This is to understand the molecular mechanism of epileptogenesis and to identify the potential diagnostic biomarkers for therapeutic targets of epilepsy. For better understanding of molecular mechanism of drug resistance epilepsy (DRE), and what scientist did they do whole genome transcriptomic analysis approach to identify genes involved in pathophysiology of DRE. In this molecular mechanism scientist found that various kinases involved in phosphorylation of microtubule-associated proteins (MAPs), glycogen synthase kinase-3 beta (GSK3β), cyclin-dependent kinase 5 (CDK5), MAP kinases were abnormally expressed. 

Seizures induced alterations of synaptic plasticity including neuronal sprouting (in which neurons grow and new nerve endings to reconnect neurons), reorganization of synapse, neurogenesis and gliosis (damage in glial cells in CNS) can result in abnormal neural network. And result in loss of inhibitory effect of endogenous antiepileptic system. Because of this the inhibitory effect of endogenous antiepileptic system not work properly, and gradually leading to development of drug resistance epilepsy (DRE). During this molecular studies scientist find out the neuropeptides such as somatostatin (SST), neuropeptide Y (NPY), galanin and many more this neuropeptide has a endogenous antiepileptic activity, modulation of synaptic plasticity will lead to modulation of neurotransmission which is crucial for memory formation as well as higher perception in the central nervous system (CNS). 

This blog is mainly focused on the role of CDK5 in synaptic transmission and suggests that altered CDK5 functions in epilepsy patients may affect the synaptic transmission, thereby contributing to the process epileptogenesis. 

Role of cyclin-dependent kinase 5 (CDK5) in neuronal function 

CDK5 is a unique multi-function proline-directed serine/threonine kinase which is activated by two non-cyclin activators, p35 and p39. CDK5/p35 complex bound to membrane in inactive form. Myristolyated p35 or p39 leads to recruitment of CDK5 to cellular membrane of dendrites. Cleavage of p35 into p25 affects its activity and CDK-p25 complex phosphorylate some nucleus proteins which leads to activation of some nuclear genes. For finding the region which is affected by CDK5 scientist use CDK5-null mutants indicated precise understanding that cerebral cortex, cerebellum and hippocampal regions are most affected areas.

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Fig. physiological and pathological condition in epilepsy and CDK5 and p35 role

This also show CDK5 have multiple neuronal functions including neuronal survival and migration, neurite outgrowth, synaptic vesicle cycle, synaptic transmission and plasticity. And CDK5 use vast variety of CDK5 substrates. CDK5 is also linked to neuronal death in Alzheimer’s and Parkinson’s disease and play important role in pathophysiology of these neurodegenerative disease. 

Role of cyclin-dependent kinase 5 (CDK5) in abnormal synaptic transmission associated with epilepsy.

CDK5 function in synaptic vesicle cycle: CDK5 phosphorylates various substrates such as synapsin 1, Munc18, Sept5, calcium/calmodulin-dependent serine protein kinase 3, Pctaire 1 this all play an important role in synaptic vesicle cycle. CDK5 regulates clathrin-mediated endocytosis by phosphorylation various substrates including amphiphysin 1, dynamin 1 etc. There is evidence showing implication of CDK5 in the inhibition of dopamine (DA) release in striatum, so deregulation of CDK5 may result in excessive release of neurotransmitter leading to epileptogenesis.   

Modulation of neurotransmitter receptors at glutamaterigic synapses: scientist find out that alteration in excitatory (glutamatergic) and inhibitory (GABAergic) synaptic transmission involve in epileptogenesis. And involvement of CDK5 in modulation of glutamatergic neurotransmission has been reported. Kainic acid (KA) induced activation of CDK5 in cultured hippocampal neurons and CDK5 also involve in influence the clustering of PSD95 complexes and regulate trafficking of metabotropic Glutamate receptors and N-methyl-d-aspartate receptor (NMDAR) subunits. CDK5 interact with various receptors and mainly needed to maintain homeostasis during increased excitotoxicity by negative regulation of the synaptic activity.                                                                                                        

  CDK5 also modulates expression of neurotransmitter receptors at the synapse, CDK5 upregulates GABA receptors transcription in CNS by phosphorylation of transcription factor and activation of STAT3 pathway. CDK5 also regulated MEF2 pathway this pathway linked with neuronal death and also in the death of dopaminergic neurons in Parkinson disease. Thus, deregulation of CDK5 affecting neurotransmitter receptor transcription at the synapse may be another possible mechanism leading to epileptogenesis.

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Fig: how CDK5 interact with different receptors in postsynaptic terminus

ROLE OF CDK5 IN EPILEPTOGENESIS

Epileptogenesis is the process of generation of chronic seizures driven by neuronal trauma/stroke. The process of epileptogenesis is includes include events cell death, cell survival and functions related to synaptic plasticity including neuronal death, neuronal migration, axonal sprouting and gliosis, and possibilities of abnormalities in different signaling mechanisms can be responsible for epilepsy. CDK5 is a adjustable kinase with multiple neuronal functions. CDK5 maintain the homeostatic plasticity in neural circuit, it is necessary in prevention of epilepsy by maintaining a balance between excitatory and inhibitory neurotransmission. Deregulation of CDK5 may cause excitotoxic damage. 

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Fig: flow chart showing how glutamatergic activation leads to prove that CDK5 role in epilepsy

Glutamatergic activation of NMDAR and AMPAR cause increase in Ca2+ concentration, which activate calpain to convert p35 to p25 leading to increase in CDK5 which causes abnormality in neuronal excitability by mis-localization and prolonged activity scientist found reports showing aberrant excitatory feedback circuit and cause seizures therefore cdk5 role in seizure activity. In normal condition CDK5 inhibit abnormal epileptiform activity. 

Cyclin-dependent kinase 5 (CDK5) as a potential prognostic/diagnostic biomarker

A biomarker is defined as highly sensitive, specific and easily measured molecular alternations of a normal or pathological condition in biological media such as human tissues, cells or fluids. Epilepsy is a multifactorial associated disease so scientist requires a biomarker to confirm the disease. Molecules associated with epileptogenesis and ictogenesis (generation of seizures) have a single common set of biomarkers for all epilepsies. The present epileptic biomarkers include imaging and electrophysiological measurements. The molecular mechanism of DRE still not clear but could be contributing in part for the lack of biomarkers for DRE (Drug resistance epilepsies). 

It has been shown that long-term but not acute loss of CDK5 activity can lead to increased Mg2+ -sensitive potentials. CDK5 is proposed to activated as a homeostatic mechanism to attenuated epileptiform activity. It is important to do studies in human brain tissue form human shows alternations in the mRNA levels of CDK5, currently anticonvulsant therapeutics is used to target voltage-gated Na+ channels or T-type Ca2+ channels. These drugs are effective in only 70 percent of adults suffering from recurrent seizures and also associated with undesired side effects. Numerous CDK5 inhibitors have been shown to be neuroprotective in both neuronal cell cultures and animal models. Roscovitine and olomoucine show suppress in ischaemia-induced tau and ischemia-induced reactive astrogliosis, they support the idea that CDK5 could be potential drug target in various neurological disorders. 

Conclusions

CDK5 has significant implications in regulating synaptic plasticity and as alterations of synaptic plasticity lead to epileptogenesis, deregulation of CDK5 mediated altered synaptic transmission may lead to epileptogenesis. Targeting the CDK5 might prove beneficial for the treatment of neurodegeneration and hyperexcitability observed in epilepsy. Being a main regulator of homoeostatic plasticity, CDK5 may play a crucial role in pathophysiology of DRE and also serve as a diagnostic biomarker of DRE.

Reference:

Dixit, A.B., Banerjee, J., Tripathi, M., Sarkar, C. and Chandra, P.S., 2017. Synaptic roles of cyclin-dependent kinase 5 & its implications in epilepsy. The Indian journal of medical research145(2), p.179.

This Post Has One Comment

  1. Lys Marie

    Despite being a complex subject for me (many terms that I don’t know about it), the way of write is excellent. It makes me want to do more research about the topic, by the way, a very interesting topic. Keep going!!

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