Heads of Laboratories
Dr. Greengard’s laboratory aims to understand the molecular basis of communication between neurons in the mammalian brain, elucidate the molecular defects responsible for various neurological and psychiatric disorders and determine the molecular mechanisms by which neuro- and psychoactive drugs produce their pharmacological actions. Over the last three decades, his lab has shown that errors in the biochemical steps that underlie this communication between neurons play a role in disorders as varied as Alzheimer’s disease and depression.
Dr. Greengard and his colleagues have shown that nerve cells communicate with each other through two mechanisms: fast and slow synaptic transmission. Fast-acting neurotransmitters, including glutamate (which is excitatory) and GABA (which is inhibitory), achieve effects on their target cells within one millisecond by virtue of opening ligand-operated ion channels. In contrast, the effects of the biogenic amines and peptide neurotransmitters, as well as some of the effects of the fast-acting neurotransmitters, are achieved over hundreds of milliseconds to minutes by slow synaptic transmission, which is mediated through a more complicated sequence of steps. Researchers in the laboratory use a multidisciplinary approach to study neuronal function and signal integration.
The Greengard lab is elucidating the signal transduction pathways through which dopamine and other neurotransmitters elicit physiological effects on their target neurons in the basal ganglia: At least a dozen neurotransmitters that regulate the activity of these neurons do so in large measure by regulating the phosphorylation of a pivotal signaling switch called DARPP-32 (dopamine and cyclic AMP-regulated phosphoprotein, Mr32kDA). DARPP-32 is the first known example of a molecule that can act either as a protein kinase or phosphatase inhibitor.
The lab has clarified much of the signaling machinery involved in the action of dopamine and other neurotransmitters that interact with the dopamine pathway, elucidated new principles of signal transduction and identified new targets for the development of drugs to treat several major psychiatric and neurological disorders. DARPP-32 provides a molecular mechanism by which all efferent information from the striatum is integrated and converted into a meaningful physiological response. Dr. Greengard’s research indicates that the essential role of DARPP-32 in cell signaling in the brain extends far beyond the dopamine signaling system and appears to involve a large number of neurotransmitters in many brain regions.
The enzyme γ-secretase catalyzes the formation of, among other vital products, amyloid-β, the substance responsible for the death of nerve cells in Alzheimer’s disease. The Greengard group recently discovered a protein that they call γ-secretase activating protein (GSAP), an essential cofactor for γ-secretase. Inhibitors of GSAP prevent the formation of amyloid-β but do not affect the formation of these 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.
Dr. Greengard and his colleagues showed that the protein p11 increases the concentration of the serotonin 1B and 4 receptors (5HT1B and 5HT4) at synapses, thereby increasing the efficiency of serotonin signaling. The interaction between p11 and 5HT1B appears to play a key role in regulating an individual’s susceptibility to depression and response to antidepressant treatments.
Other research from Dr. Greengard’s lab provides evidence for an essential role of genome-encoded microRNAs in survival of differentiated neurons. Loss of the key microRNA-generating enzyme Dicer leads to Purkinje cell death, which bears obvious similarity to processes associated with such slow-progressing neurodegenerative diseases as Alzheimer’s and Parkinson’s.
Dr. Greengard, in collaboration with Nathaniel Heintz’s laboratory, developed a method to identify translational profiles by isolating the genetic messages that govern protein production in different cell types. The new method, translating ribosome affinity purification, uses genetically engineered mice to capture these messages as they pass through ribosomes. The researchers identified 24 types of cells in the central nervous system, identifying thousands of proteins previously unassociated with known cell types.
A collaboration with Alexander Tarakhovsky’s laboratory showed that ablation of the epigenetic regulator GLP/G9a in specific neuronal cell types in mice caused impairment similar to a mental retardation syndrome in humans called the 9q34 deletion syndrome.
Dr. Greengard received his Ph.D. in biophysics from The Johns Hopkins University in 1953. Before joining Rockefeller in 1983 as a 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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