Molecular Mechanisms of Presynaptic Assembly

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DESCRIPTION (provided by applicant): Development of the brain into a functional unit is undoubtedly one of the greatest engineering feats of nature. Aim of this project is to contribute to our understanding of the mechanisms that underlie this developmental process. More specifically, experiments outlined in this application aim to understand development of synapses. Chemical synapses are functional units that are indispensable for neural communication. Although we know much about the various functional aspects of synapses, we know very little about the molecular mechanisms that underlie synapse formation. Insights gained into the molecular architecture of synapses and its maintenance will take us at least towards understanding, if not curing neural diseases, especially degenerative diseases such as Alzheimer's. In order to understand the molecular framework of synaptic assembly, we utilized C. elegans, which is very amenable to making transgenic and knockout animals. We have systematically investigated and uncovered a three-layer molecular hierarchy of presynaptic assembly in vivo in C. elegans. First, a transmembrane protein, SYG-1 specifies the location of presynaptic sites. Next, SYG-1 recruits two key scaffold molecules SYD-1 and SYD-2 that are essential for synapse formation. Finally, these scaffold proteins recruit numerous components including synaptic vesicles. Now that we have established a molecular framework of presynaptic assembly, we would like to gain mechanistic insights into the development of this framework. In Aim 1, we will characterize the interaction between SYG-1 and SYD-1. Preliminary evidence indicates that SYD-2 is intra- and inter-molecularly regulated. In Aim 2, we propose to genetically and biochemically test this regulation. Finally, SYD-2 has been shown to directly interact with KIF1 A, a kinesin that transports synaptic vesicles from the cell body to the synapses. In AIM 3, we propose to test the prediction that SYD-2 is important for unloading of vesicular cargo from KIF1A at the synapses. We live in a time when preventive measures and sophisticated medical technology have made it possible for us to live longer than at any time during our history. However, later years of life are often associated with degenerative diseases, especially neurological ones. If we are to get most out of later years of our life, it will be essential for us to understand and eventually cure neurodegenerative diseases. Research proposed in this application takes a small step towards achieving this goal.