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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS059953-02
Application #
7482985
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Talley, Edmund M
Project Start
2007-08-15
Project End
2012-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
2
Fiscal Year
2008
Total Cost
$357,656
Indirect Cost
Name
Tufts University
Department
Physiology
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
Moss, Benjamin J; Park, Lidia; Dahlberg, Caroline L et al. (2016) The CaM Kinase CMK-1 Mediates a Negative Feedback Mechanism Coupling the C. elegans Glutamate Receptor GLR-1 with Its Own Transcription. PLoS Genet 12:e1006180
McGehee, Annette M; Moss, Benjamin J; Juo, Peter (2015) The DAF-7/TGF-? signaling pathway regulates abundance of the Caenorhabditis elegans glutamate receptor GLR-1. Mol Cell Neurosci 67:66-74
Garafalo, Steven D; Luth, Eric S; Moss, Benjamin J et al. (2015) The AP2 clathrin adaptor protein complex regulates the abundance of GLR-1 glutamate receptors in the ventral nerve cord of Caenorhabditis elegans. Mol Biol Cell 26:1887-900
Dahlberg, Caroline L; Juo, Peter (2014) The WD40-repeat proteins WDR-20 and WDR-48 bind and activate the deubiquitinating enzyme USP-46 to promote the abundance of the glutamate receptor GLR-1 in the ventral nerve cord of Caenorhabditis elegans. J Biol Chem 289:3444-56
Kowalski, Jennifer R; Dube, Hitesh; Touroutine, Denis et al. (2014) The Anaphase-Promoting Complex (APC) ubiquitin ligase regulates GABA transmission at the C. elegans neuromuscular junction. Mol Cell Neurosci 58:62-75
Goodwin, Patricia R; Juo, Peter (2013) The scaffolding protein SYD-2/Liprin-? regulates the mobility and polarized distribution of dense-core vesicles in C. elegans motor neurons. PLoS One 8:e54763
Monteiro, Michael I; Ahlawat, Shikha; Kowalski, Jennifer R et al. (2012) The kinesin-3 family motor KLP-4 regulates anterograde trafficking of GLR-1 glutamate receptors in the ventral nerve cord of Caenorhabditis elegans. Mol Biol Cell 23:3647-62
Kowalski, Jennifer R; Juo, Peter (2012) The role of deubiquitinating enzymes in synaptic function and nervous system diseases. Neural Plast 2012:892749
Goodwin, Patricia R; Sasaki, Jennifer M; Juo, Peter (2012) Cyclin-dependent kinase 5 regulates the polarized trafficking of neuropeptide-containing dense-core vesicles in Caenorhabditis elegans motor neurons. J Neurosci 32:8158-72
Kowalski, Jennifer R; Dahlberg, Caroline L; Juo, Peter (2011) The deubiquitinating enzyme USP-46 negatively regulates the degradation of glutamate receptors to control their abundance in the ventral nerve cord of Caenorhabditis elegans. J Neurosci 31:1341-54

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