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Paul Greengard
Vincent Astor Professor

The goal of our laboratory is to understand more fully the molecular basis of communication between neurons in the mammalian brain. Toward this end, we have developed a general model of signal transduction in the nervous system. The major molecular mechanism underlying signal transduction is protein phosphorylation.

Synaptic Vesicle-associated Phosphoproteins. The major synaptic vesicle-associated phosphoproteins that we have identified and characterized are synapsin I, synapsin II, and synaptophysin. As an example of the functioning of this class of phosphoproteins, we have obtained evidence that dephosphorylated synapsin I functions to tether synaptic vesicles in a "reserve" pool. When synapsin I is phosphorylated, this tethering function is abolished, and the synaptic vesicles are then free to enter a "readily releasable" pool of synaptic vesicles. Additionally, we have obtained evidence that the synapsins are involved in the formation of new synapses.

Neostriatum-enriched Phosphoproteins. The neostriatum comprises an anatomic area of both basic and clinical interest because of its high concentration of dopaminergic neurons and receptors, which have been implicated in the pathophysiology of a number of diseases including Parkinson's disease and schizophrenia. One example of a neostriatum-enriched phosphoprotein is DARPP-32. DARPP-32 plays a general role as an integrating mechanism for multiple incoming neurotransmitter signals in the neostriatum, being phosphorylated by some neurotransmitter pathways and dephosphorylated by others. The phosphorylated form, but not the dephosphorylated form, of DARPP-32 inhibits a protein phosphatase which in turn controls the activity of various ion pumps and channels. Thus, the actions of numerous neurotransmitters in producing physiological effects in these neurons can be accounted for in terms of a complex signal transduction cascade.

Signal Transduction and Cerebral Amyloidosis in Alzheimer's Disease. In Alzheimer's disease, characteristic structural changes develop in the brain, including the formation of extracellular amyloid deposits. The amyloid deposits result from the metabolism of a large integral protein, the amyloid precursor protein (APP), to a fragment known as /A4. A variety of clinical observations and laboratory evidence suggests that amyloidogenesis plays a central role in the clinicopathological syndrome.

We have demonstrated that activators of protein kinase C and inhibitors of protein phosphatases 1 and 2a dramatically reduce the formation of /A4, providing a potential route to the prevention of Alzheimer's disease. Studies are under way to define the cellular itinerary of APP, to characterize the enzymes which constitute the normal and amyloidogenic pathways of APP catabolism, and to establish the molecular mechanisms by which alterations of protein phosphorylation control the formation of /A4.

Publications
Publications