Mario Tiberi, PhD
mtiberi@uottawa.ca
The fact that schizophrenia and Parkinson's disease have something in common might seem surprising, and perhaps unimportant even to those who suffer from these afflictions. Yet there is a connection: dopamine, a type of chemical called a neurotransmitter that the brain uses to send signals. A better understanding of this signalling process will lead simultaneously to greater knowledge of the malfunctions that underlie both of these disorders, thus allowing the design of better, more specific drugs to treat them. Our understanding of drug addition will also be increased, as it has recently become clear that dopamine plays a role here, as well. Therefore, it is on the question of how the brain uses dopamine to transmit signals that Dr. Mario Tiberi focuses his attention.
Dopamine works by attaching itself to a specific proteins called receptors that are found on the outside of the brain cell. Five genes are known to code for these receptors. The binding of a dopamine molecule with a receptor initiates a cascade of biochemical events inside the cell. Dr. Tiberi is investigating how these receptors work, how dopamine binds to them, and how information is thus transmitted from outside the cell to inside.
The drugs currently available for Parkinson's or schizophrenia patients also work by binding to dopamine receptors. But because the differences between individual receptors are not yet well understood, these drugs are not specific enough. As a result, patients who take these drugs for an extended period of time may develop side effects. Thus, Dr. Tiberi and his team have taken on several challenges. First, they hope to determine what it is that makes the various dopamine receptors different from each other, in terms of how they recognise and bind dopamine and other dopamine-related drugs. In a related line of inquiry, they are investigating how, once the dopamine complex has formed, it regulates the signaling inside the cells. They are also studying the effects of short- and long-term exposure on these receptors. If long-term treatment with a given drug causes receptors to become less responsive, the drug's effectiveness becomes compromised. This can be a problem, as schizophrenia and Parkinson's patients can expect to take these drugs for their entire lives. Thus, finding the answers to these questions will represent a decisive step forward in the development of more selective drugs.
For this particular research, Dr. Tiberi and his team are using cells in culture, into each of which they have transferred one of the five genes that codes for a dopamine receptor. Then, they add dopamine or a dopamine-related drug, and study the biochemical and biological consequences. To study long-term effects, they expose these cells to a particular drug for different lengths of time. They then assess the stability and functionality of the receptor proteins to determine if the binding and signalling are the same as they were prior to exposure, or what effects short-term or long-term exposure may have. If the receptor proteins are still as responsive as ever, no matter how long the exposure was, that is some indication that the drug will remain effective even if taken for a lifetime.
Another technique the team uses is to modify the dopamine receptor genes in order to change the receptor structure. Observing the results of these changes will help them understand how normal receptors function. Dr. Tiberi is also interested in how these drugs act to alleviate the symptoms of these diseases--something that is not yet known. Understanding these different aspects of how the receptor and drug interact will help illuminate how the diseases work in the first place. That may lead to the discovery of a defect in one of the pathways that regulates the whole receptor cascade, thus filling out the picture of exactly what goes wrong in Parkinson's or schizophrenia, or even in drug addiction.
Battling a chronic illness is challenge enough without the added agony of debilitating side- effects conferred by the very medication that is meant to provide relief. It is the painstaking work of researchers like Dr. Tiberi that offers both our best hope of understanding these diseases, and the most direct avenue to the novel therapeutics that will bring relief to all those who suffer from them.
