Heads of Laboratories
The Greengard laboratory studies the molecular defects responsible for neurological and psychiatric disorders including Alzheimer’s disease, Parkinson’s disease, schizophrenia and major depressive disorder, as well as the molecular mechanisms by which neuro- and psychoactive drugs produce their pharmacological actions in these disorders.
Research from the Greengard laboratory has demonstrated that most neurotransmitters and neuromodulators achieve their actions and interactions on postsynaptic neurons through a process called “slow synaptic transmission.” This process involves activation of highly complex signal transduction cascades. For the last 10 years, the group has applied this knowledge to the study of the molecular pathways behind various neurological and psychiatric disorders.
One major area of activity in the Greengard laboratory involves a search for the molecular and cellular basis of major depressive disorder (MDD). They recently found a protein called p11 (S100A10, a member of the S100 family of proteins) that plays a central role in the regulation of mood. Constitutive removal of p11 from neurons in the brain causes a depressive phenotype and a loss of behavioral response to antidepressant agents. Deletion of p11 from one cell type in the nucleus accumbens causes the depressive phenotype, and deletion from any of three other cell types results in the loss of behavioral responses to antidepressants. The antidepressant action of p11 is mediated through binding of p11 to a chromatin-remodeling factor, SMARCA3. SMARCA3, in turn, through activation of various transcription factors, regulates gene transcription. One current project of the research group is to determine which of these genes is necessary for the therapeutic actions of various antidepressants and to determine the molecular mechanisms of action of these gene products.
A second major area of interest of the laboratory is the analysis of the enzymatic pathways involved in the synthesis and degradation of amyloid-β, the prime suspect in the etiology of Alzheimer’s disease. The enzyme γ-secretase catalyzes the formation of amyloid-β, the substance believed to be responsible for the death of nerve cells in Alzheimer’s disease. In addition, γ-secretase catalyzes the formation of notch and of many other proteins vital to cell function. The group has recently discovered a protein, which they named γ-secretase activating protein (GSAP), which selectively activates the catalytic formation of amyloid-β by γ-secretase, but not of notch. As a result, inhibitors of GSAP selectively prevent formation of amyloid-β without affecting formation of notch and other vital products. Therefore, GSAP represents a singularly attractive target for the development of drugs to inhibit amyloid-β formation and thus prevent Alzheimer’s disease, without toxic side effects. In other studies in the laboratory, two pathways involved in regulation of amyloid-β degradation have been found, and the mechanisms by which these pathways achieve their effects are being investigated.
A third area of activity of the laboratory involves determining the molecular basis for the differences between vulnerable cells and non-vulnerable cells in Alzheimer’s disease and in Parkinson’s disease. This approach is based on identifying all expressed proteins in individual nerve cell types in the brain using bacTRAP technology, which was developed in collaboration with Rockefeller’s Nathaniel Heintz. Proteins that are highly expressed in vulnerable cells are being introduced to non-vulnerable cells to see if they cause vulnerability. Conversely, proteins that are highly expressed in non-vulnerable cells are being introduced to vulnerable cells to see if they afford protection.
Dr. Greengard received his Ph.D. in biophysics from The Johns Hopkins University in 1953. Before joining Rockefeller in 1983 as Vincent Astor Professor and head of laboratory, he was director of biochemical research at the Geigy Research Laboratories and a professor of pharmacology and psychiatry at Yale University. Since 1995 he has also directed the Fisher Center for Alzheimer’s Disease Research at Rockefeller.
Dr. Greengard is a member of the National Academy of Sciences (NAS) and the American Academy of Arts and Sciences. Among his many awards and honors are the Gold Medal of the Karolinska Institute, the 2000 Nobel Prize in Physiology or Medicine, the 1997 Charles A. Dana Award for Pioneering Achievements in Health and the 1991 NAS Award in the Neurosciences.
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