A multi-disciplinary approach is proposed in this Program Project to identify and characterize the basis by which the synapsin family of phosphoproteins promote synaptogenesis and stabilize synapses. A greater understanding of the molecular mechanisms which underlie the trophic actions of the synapsins may lead to novel therapeutic targets for the treatment of Alzheimer's disease. To define the trophic function of the synapsins in synapse formation and maintenance, studies will be performed at several levels of organization complexity, encompassing in vitro biochemical studies with purified molecules, cell biological systems, and studies in intact animals Project I will focus on elucidating the mechanisms by which the synapsins regulate the temporal expression and spatial organization of cytoskeletal and synaptic proteins during synaptogenesis and synapse stabilization. Immunocytochemical and biochemical analyses will be used to assess the effects of targeted deletion of the synapsins, and the expression of mutant synapsins, in primary neuronal cultures. Project II will characterize the mechanisms by which the synapsins act as downstream effectors in the signal transduction cascade that is activated by the neurotrophins. The phosphorylation of the synapsins by MAP kinase, the physiological regulation of this kinase by the neurotrophins, and the functional consequences of this phosphorylation will be studied in vitro and in vivo. Project III will examine the effects of altered synapsin expression on neural degeneration and reactive synaptogenesis in animal models. We will compare wild-type mice with aged mice and with which have been experimentally modified by targeted genetic alterations and by physical/chemical insults. A Core facility will provide a range of technical support services to the other components of the Program Project. The Core will be responsible for the preparation and maintenance of key reagent, and will maintain the colonies of genetically altered mice.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG015072-02
Application #
2871460
Study Section
National Institute on Aging Initial Review Group (NIA)
Project Start
1998-02-15
Project End
2003-01-31
Budget Start
1999-02-01
Budget End
2000-01-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Rockefeller University
Department
Other Basic Sciences
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Giovedi, Silvia; Darchen, Francois; Valtorta, Flavia et al. (2004) Synapsin is a novel Rab3 effector protein on small synaptic vesicles. II. Functional effects of the Rab3A-synapsin I interaction. J Biol Chem 279:43769-79
Giovedi, Silvia; Vaccaro, Paola; Valtorta, Flavia et al. (2004) Synapsin is a novel Rab3 effector protein on small synaptic vesicles. I. Identification and characterization of the synapsin I-Rab3 interactions in vitro and in intact nerve terminals. J Biol Chem 279:43760-8
Porton, Barbara; Kao, Hung-Teh (2003) Effect of protein phosphorylation on neurite outgrowth in cultured embryonic Xenopus spinal neurons. Neurosignals 12:45-52
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Menegon, Andrea; Verderio, Claudia; Leoni, Chiara et al. (2002) Spatial and temporal regulation of Ca2+/calmodulin-dependent protein kinase II activity in developing neurons. J Neurosci 22:7016-26
Pieribone, Vincent A; Porton, Barbara; Rendon, Beatrice et al. (2002) Expression of synapsin III in nerve terminals and neurogenic regions of the adult brain. J Comp Neurol 454:105-14
Kao, Hung-Teh; Song, Hong-jun; Porton, Barbara et al. (2002) A protein kinase A-dependent molecular switch in synapsins regulates neurite outgrowth. Nat Neurosci 5:431-7
Humeau, Y; Doussau, F; Vitiello, F et al. (2001) Synapsin controls both reserve and releasable synaptic vesicle pools during neuronal activity and short-term plasticity in Aplysia. J Neurosci 21:4195-206
Cheetham, J J; Hilfiker, S; Benfenati, F et al. (2001) Identification of synapsin I peptides that insert into lipid membranes. Biochem J 354:57-66

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