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| Laboratory of Molecular and Cellular Neuroscience |
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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.
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