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. In addition, the lab investigates 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 underlying 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. In one current project, the lab is determining which of these genes is necessary for the therapeutic actions of various antidepressants and the molecular mechanisms of action of these gene products.
A second major area of interest 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 now being investigated.
A third area of the laboratory’s activity 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 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.