The long-term goal of this research is to identify and understand the genes and mechanisms that regulate CDK-5 function in synaptic transmission. The cyclin-dependent kinase CDK-5 has diverse cellular functions during development, contributes to several neurodegenerative disorders, and has recently emerged as an important regulator of synapse function and plasticity. The focus of this proposal is to investigate the mechanisms by which CDK-5 regulates glutamate receptor (GluR) trafficking and to identify upstream regulatory signals that control CDK-5 function at the synapse. Activity-dependent regulation of the localization and abundance of synaptic GluRs directly affects synaptic strength and is thought to underlie information storage and processing in the brain. Aberrant regulation of GluRs may contribute to excitotoxicity in ischemia (lack of blood flow), stroke and neurodegenerative disorders. Thus, it is important to define the basic cell biological mechanisms that regulate GluR transport. We use C. elegans as a genetic model to study the genes and mechanisms that regulate synaptic transmission and GluR trafficking in vivo. Advantages of C. elegans include the compact genome (i.e. less gene redundancy), powerful genetic tools and ability of the animal to tolerate severe reductions in nervous system function. Our preliminary studies indicate that CDK-5 regulates the abundance of the scaffolding protein LIN-10/Mint-1 and the glutamate receptor GLR-1 at synapses in vivo. LIN-10/Mint-1 is a PTB and PDZ domain-containing protein that has been localized to the golgi and synapses and has a conserved role in polarized transport in neurons and epithelia. In this proposal, we will (1) Determine which step of GLR-1 trafficking is regulated by CDK-5, (2) Define the mechanisms by which CDK-5 regulates the abundance of LIN-1u/Mint-1, (3) Characterize the upstream regulatory signals that control CDK-5 function. This research may reveal novel targets for therapeutic intervention to control GluR-mediated excitotoxicity after stroke and ischemic (lack of blood flow) brain injury. In addition, since CDK-5 regulates neuronal development and function, and contributes to Alzheimer's Disease and amyotrophic lateral sclerosis (ALS), understanding the mechanisms that regulate CDK-5 activity and how it controls synaptic transmission in healthy neurons will help reveal the pathogenesis underlying the role of CDK-5 in neurodegeneration. ? ?
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