Regulation of glutamate receptors at synapses by WD40 repeat proteins and the deubiquitinating enzyme USP-46 in C. elegans

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This project will increase our fundamental understanding of how neurons communicate with each other at the molecular level. Neuronal communication is essential for normal brain function and for learning and memory. Neurons communicate with each other at specialized junctions called synapses. Neurons release chemical signals, such as the neurotransmitter glutamate, which are received by downstream neurons via specialized protein detectors called glutamate receptors (GluRs). Changing the number or levels of GluRs at the synapse allows neurons to alter their communication, which enables the brain to learn, adapt and store memories. The specific focus of this project is to study how a new family of proteins control the number of GluRs at the synapse by preventing their degradation via the ubiquitin system. Ubiquitin is a tag that can be attached and removed from other proteins in a highly controlled manner. Proteins marked with ubiquitin are targeted to the cellular trash for degradation. This proposal studies how three proteins function together to specifically remove ubiquitin from GluRs, thus rescuing them from degradation and increasing receptor levels at the synapse. In addition, this project develops and launches an innovative, discovery-based Molecular Genetics and Cell Biology Lab Course for undergraduates, trains graduate students and postdoctoral fellows, and provides research opportunities for high school teachers and minority undergraduates. Ubiquitin is an important regulator of synapse development and function. There are about 100 deubiquitinating enzymes (DUBs) that remove ubiquitin from other proteins, however very little is known about the DUBs that function at the synapse. The awardee's lab recently identified USP-46 as the first DUB to regulate GluRs. This proposal investigates how two proteins, WDR-20 and WDR-48, interact and regulate the activity of USP-46 to control GluRs levels at the synapse, and tests how these molecular changes affect behavior. This study uses genetic, biochemical, quantitative imaging and behavioral methods to study GluRs in the well-established genetic model organism C. elegans. Advantages of C. elegans include powerful genetic tools, a simple and defined nervous system, and simple behavioral assays to correlate neuronal function with whole animal behavior. The basic mechanisms involved in synapse development and function are conserved from nematodes to humans. Understanding how molecular changes at the synapse impact neuronal communication and behavior will provide fundamental information that could be applied to improve learning and memory, and to begin to uncover the molecular basis of learning and behavioral disorders.