At the Institute we have been studying dopamine and the genes that regulate its production. Dopamine is a key neuromodulator that influences learning of reward-motivated behaviors, and its role in addictions is often discussed. It affects brain processes that control movement, emotional response, and the ability to experience pleasure and pain. Deficits in dopamine signaling are associated with the development of degenerative and psychiatric disorders such as Parkinson’s disease, schizophrenia, and depression.

Dopamine in the Basal Ganglia and Parkinson’s Disease
Dopamine deficit in the structures in the brain called basal ganglia has been associated with a number of neurodegenerative diseases including Parkinson’s disease and Huntington’s chorea. At the Institute we have been studying the effects of several different drugs on the generation of dopamine receptors in the basal ganglia. These drugs include caffeine, haloperidol, bromocriptine mesylate or BCM (anti-Parkinsonian drug), and clozapine (anti-psychotic). Our results indicate that caffeine increases the formation of dopamine receptor called D2R, while both BCM and clozapine decrease D2R receptor formation. The changes in the number of receptors were more significant in case of female subjects. This result indicates a very significant level of difference for the impact of these drugs on males vs. females, and suggests that dosages of these drugs prescribed could be gender-specific.

Proteomic Approach to Parkinson’s Disease
Recent studies show that coffee drinkers are less likely to develop Parkinson’s disease (PD), which is caused by degeneration of dopamine producing neurons. The cause of neuronal death is not well understood, but seems to be related to mitochondrial dysfunction. Caffeine seems to protect these neurons. At the Institute we have identified several proteins whose levels are regulated by dopamine. One of these, cytochrome oxidase affects synthesis of ATP (necessary for cell metabolism), which is dependent on the proper function of mitochondria. We study how cytochrome oxidase levels control metabolic rate and ultimately cell physiology and death. Neuronal death in PD is accelerated by the presence of metabolic and/or oxidative stress. Levels of ATP in cells have a strong correlation to the development of potassium channels in the membrane that may serve to protect the cell. We are interested in molecular mechanisms whereby antioxidant properties of drugs like caffeine protect dopamine producing neurons, hence reducing chances of development of PD.

Rett Syndrome
Rett syndrome is a neurological disorder primarily affecting females. Affected individuals often exhibit autistic-like behavior. One in 10-15,000 births are affected. It has been found that defect in the gene responsible for producing a protein called MeCP2 is involved in Rett syndrome. We have found that mild over-expression of MeCP2 protein in mice can cause severe motor dysfunction. At the Institute we are investigating how expression of MeCP2 is regulated, and are preparing proposals to explore the usage of viral methods for gene therapy which may potentially lead to treatment or cure for Rett syndrome.

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