Dr. Greengard’s laboratory is also elucidating the signal transduction pathways through which dopamine and other neurotransmitters elicit physiological effects on their target neu-rons in the basal ganglia. They have found that at least a dozen neurotransmitters that regulate the activity of these neurons do so in large measure by regulating the state of phosphorylation of a pivotal signaling switch referred to by the acronym 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.

Dr. Greengard’s lab has clarified much of the signaling machinery involved in dopamine action and the action of other neurotransmitters that interact with the dopamine pathway, has elucidated new principles of signal transduction and has provided a variety of new targets for the development of drugs for the treatment of several major psychiatric and neurological disorders. DARPP-32 provides a molecular mechanism by which all efferent information is integrated and converted into a meaningful physiological response. Research by Dr. Greengard and his colleagues indicates that the essential role of DARPP-32 in cell signaling in the brain extends far beyond the dopamine cell signaling system and appears to involve a large number of neurotransmitters in many brain regions.

The Greengard lab also demonstrated that the relative amounts of Alzheimer amyloid precursor protein (APP) that are converted to the nontoxic soluble form of APP (APPs) and the toxic amyloid- are controlled by protein phosphorylation and dephosphorylation mechanisms. Thus, activators of various protein kinases, as well as inhibitors of various protein phosphatases, reduce the amount of amyloid- formed by nerve cells. Work is now under way in his lab to determine the components of the signal transduction cascade that are responsible for the regulation of APP breakdown and the formation of amyloid-, with the aim of developing new targets for the treatment of Alzheimer’s disease.

Dr. Greengard and colleagues identified the protein p11 as a regulator of serotonin signaling in the brain. The researchers showed that p11 increases the concentration of the serotonin 1B receptor at synapses, thereby increasing the efficiency of serotonin signaling. The interaction between p11 and the serotonin 1B receptor appears to play a key role in an individual’s susceptibility to depression and his or her response to antidepressant treatments.

New research from Dr. Greengard’s lab provides evidence for an essential role of genome-encoded microRNAs (miRNAs) in survival of differentiated neurons. The researchers show that conditional Purkinje cell-specific ablation of the key miRNA-generating enzyme Dicer leads to Purkinje cell death. Deficiency in Dicer is associated with progressive loss of miRNAs followed by cerebellum degeneration and development of ataxia. This pattern of Purkinje cell degeneration in the absence of miRNAs bears obvious similarity to processes associated with such slow progressing neurodegenerative diseases as Alzheimer’s and Parkinson’s.

CAREER

Dr. Greengard received his Ph.D. in biophysics from 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 at Yale University. Since 1995, he has directed the Fisher Center for Research on Alzheimer’s Disease at Rockefeller.

Dr. Greengard is a member of the U.S. National Academy of Sciences and the American Academy of Arts and Sciences. Among Dr. Greengard’s many awards and honors are the 2000 Nobel Prize in Physiology or Medicine, the 1998 Mayor’s Award for Excellence in Science or Technology and the 1997 Charles A. Dana Award for Pioneering Achievements in Health.