October 5, 2010

Protein Research Improves Study of Neuropharmacology

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Imagine a full-operational subway car, carrying employee to and from the business district of a major city.  The operation of these businesses depends largely upon the arrival and number of these necessary workers – if the cars were only half-filled during the commute, the business would function only partly as well.

Like subway cars, neurons carry molecules –­­ or neurotransmitters – which coordinate signals across the body. But like a subway car transporting too few workers, neurons may fail to maximize their efficiency.  Sometimes, neurons release only a fraction of their available neurotransmitters, and their signals propagate less efficiently than they should, resulting in some neurological conditions.

A recently published study by Weill Cornell indicates that researchers have wiretapped the elusive communication system of neurons, allowing us to pharmacologically boost signaling in cases of neurodegeneration, such as that associated with Parkinson’s disease. This work shows that one specific protein – cyclin-dependent kinase 5 (CDK5) – hugely impacts the number of neurotransmitters conveyed to neighboring neurons.

CDK as a neuron’s caffeine

Synaptic vesicles – sacs in neuron cells – store neurotransmitters that relay the messages through the nervous system.   Recent Weill Cornell research examined the reserve pool, which only releases signal molecules when stimulation surpasses normal limits. They are “on reserve” since their release requires great energy and heavy stimulation.

However, even strong stimulation may not awaken some stubborn synapses.  In order to activate these neurons, additional action is required through the inhibition of a protein, called CDK5.

CDK5 normally forces synapses to an inactive state, but inhibition of CDK5 converts resting vesicles into recycling vesicles, acting as a switch.

Inhibiting CDK5 with a drug called Roscovitine awakens previously “silent” synapses and ramps up signaling in already active synapses. This inhibition increases the number of active neurons from 50 to almost 90 percent.

Future studies on CDK5-inhibition will: identify the specific CDK5 substrate(s) that control access to the resting pool, understand how directly CDK5-CN affects vesicle turnover (does a rate-limiting step exist?), and decipher biochemically what differentiates the three vesicles pools, since they all look alike under a microscope.

CDK as Mr. Jekyll

The importance of CDK5 in the central nervous system has been known since experiments revealed that mice born mice without CDK5 die just before or after birth, largely due to poorly-migrated neurons in an improperly layered cerebral cortex, hippocampus, cerebellum, and olfactory bulb.

It is also known that CDK5 regulates other functions, including structural stability, adhesion to other molecules, and membrane transport. Research suggests that is it necessary for the progression of adult-generated neurons to maturity since it affects the survival, but not the proliferation, of the adult-generated neurons of the hippocampus.

Recent studies even suggest that CDK5 plays crucial roles in non-neuronal cells such as insulin secretion in pancreatic -cells. Thus, CDK5 inhibitors are a promising therapeutic avenue for the treatment of neurodegenerative diseases, drug abuse, and diabetes mellitus.

CDK as Mr. Hyde

However, CDK5 has a nasty side too. Jekyll becomes Hyde when either too much CDK5 accumulates, too little remains, or its binding partners switch around – this causes disease of the mammalian central nervous system. Thus, this multi-faced protein must undergo fine-tuned regulation to ensure proper brain functioning.

For example, CDK5 and its binding partner, called p25, may conjointly contribute to the formation of neurofibrillary tangles – proteins that cause Alzheimer’s disease when they aggregate in the brain. Similarly, p25 levels and CDK5-associated activity may contribute to the motor-neuron degeneration of Amytrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, which is fatal.

This research may lead to therapeutics that convert neuronal whispers into shouts, or vice versa, to save neurons and  stave off neural diseases.

Original Author: Sophia Porrino