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Heads of Laboratories

Head shot of Paul Greengard
Paul Greengard, Ph.D.
Vincent Astor Professor
Laboratory of Molecular and Cellular Neuroscience
Paul.Greengard@rockefeller.edu

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 15 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. 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. The antidepressant action of p11 is mediated through binding of p11 to a chromatin-remodeling factor, SMARCA3. SMARCA3, in turn, regulates the transcription of many genes. One current project 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. The group has recently discovered a protein, which they named γ-secretase activating protein (GSAP), that selectively regulates the trafficking of the amyloid precursor protein, APP, and the formation of amyloid-β. Reductions in the levels of GSAP prevent formation of amyloid-β. GSAP represents an attractive target for therapies to inhibit amyloid-β formation and thus prevent Alzheimer’s disease. In other studies in the laboratory, other pathways involved in regulation of amyloid-β degradation have been found, and their mechanisms of action 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 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 highly expressed in vulnerable cells are introduced to non-vulnerable cells to see if they cause vulnerability. Conversely, proteins highly expressed in non-vulnerable cells are introduced to vulnerable cells to see if they afford protection.


EDUCATION

A.B. in physics and mathematics, 1948
Hamilton College

Ph.D. in neurophysiology, 1953
Johns Hopkins University

POSTDOC

University of London, 1953–1954

Cambridge University, 1954–1955

UK National Institute for Medical Research, 1955–1958

National Institutes of Health, 1958–1959

POSITIONS

Director of Biochemical Research, 1959–1967
Geigy Research Laboratories

Professor, 1968–1983
Yale University School of Medicine

Professor, 1983–
Director, Fisher Center for Alzheimer’s Disease Research, 1995–
The Rockefeller University

AWARDS

Dickson Prize, 1977

Pfizer Biomedical Research Award, 1986

3M Life Sciences Award, Federation of American Societies for Experimental Biology, 1987

illiam R. McAlpin, Jr., Award, National Mental Health Association, 1987

Bristol-Myers Award, 1989

National Academy of Sciences Award in the Neurosciences, 1991

Karl Spencer Lashley Prize, American Philosophical Society, 1993

Ralph W. Gerard Prize in Neuroscience, 1994

Thudichum Medal, Biochemical Society, 1996

Lieber Prize in Schizophrenia Research, 1996

Charles A. Dana Award, 1997

New York City Mayor’s Award for Excellence in Science and Technology, 1998

Ellison Medical Foundation Senior Scholar Award, 1999

Nobel Prize in Physiology or Medicine, 2000

Scientific Honoree, New York Academy of Medicine, 2002

Dart/NYU Biotechnology Achievement Award, 2010

Gold Medal, Karolinska Institute, 2010

MEMBERSHIPS

National Academy of Sciences
American Academy of Arts and Sciences
American Philosophical Society
Foreign Member, Royal Swedish Academy of Sciences
Norwegian Academy of Science and Letters
Serbian Academy of Sciences and Arts

SELECTED PUBLICATIONS

Svenningsson, P. et al. Preliminary evidence that early reduction in p11 levels in natural killer cells and monocytes predicts the likelihood of antidepressant response to chronic citalopram. Mol. Psychiatry 19, 962–964 (2014).

Tan, C.L. et al. MicroRNA-128 governs neuronal excitability and motor behavior in mice. Science 342, 1254–1258 (2013).

Svenningsson, P. et al. p11 and its role in depression and therapeutic responses to antidepressants. Nat. Rev. Neurosci. 14, 673–680 (2013).

Oh, Y.S. et al. SMARCA3, a chromatin-remodeling factor, is required for p11-dependent antidepressant action. Cell 152, 831–843 (2013).

Heiman, M. et al. A translational profiling approach for the molecular characterization of CNS cell types. Cell 135, 738–748 (2008).


Dr. Greengard is a faculty member in the David Rockefeller Graduate Program and the Tri-Institutional M.D.-Ph.D. Program.