Synapses are the connections that transmit information flow in the brain. Several diseases and conditions that result in a loss of synapses or synaptic function can be thought of as "diseases of the synapse" including neurodegenerative diseases, such as Alzheimer's disease, and trauma to the central nervous system from stroke. While disease-specific therapies will be helpful, broad based therapies such as those that trigger new synapse formation or stabilize existing synapses will also be extremely valuable potentially slowing disease progression, or improving recovery following trauma or disease onset. To our knowledge there is no pharmaceutical that specifically triggers new synapse formation or stabilizes existing connections. Achieving this milestone remains a primary, pressing and urgent goal of the medical community. The first step in achieving this goal is to understand how nature builds a synapse, allowing the identification of the best therapeutic targets. The long-term goal of our research program is to identify and understand the molecular players that orchestrate synapse formation, and integrate synapse formation with other key neurodevelopmental processes, such as axon termination. Importantly, synapse formation is an evolutionarily conserved process that occurs in simple invertebrates, such as the worm C. elegans, through human beings. Thus, molecules that are critical to synapse formation will also be evolutionarily conserved. Using C. elegans as a model system, we aim to rapidly and efficiently identify conserved molecules that function in synapse formation and axon termination. While we are a long way from fully understanding how a synapse is built and maintained, it is important to emphasize that many of the molecules that are known to regulate this process were identified using C. elegans. One such molecule that regulates synapse formation, as well as axon termination, guidance and regeneration is the Regulator of Presynaptic Morphology (RPM)-1. While its key and central role as a neurodevelopmental regulatory protein potentially makes RPM-1 an ideal therapeutic target, we still have very limited knowledge on how RPM-1 functions. To gain insight into RPM-1's mechanism of action, we have recently performed a proteomic screen to identify proteins that bind to RPM-1. In this proposal, we aim to study two novel, conserved RPM-1 binding proteins that we identified in our proteomic screen, NPP-17 and T23F11.1. We will use transgenics, genetics and cell biology in C. elegans to determine if NPP-17 and T23F11.1 function in synapse formation and axon termination. We will also determine if NPP-17 and T23F11.1 mediate RPM-1 function, and how NPP-17 and T23F11.1 relate to pathways that are known to act downstream of RPM-1. Importantly, both T23F11.1 and NPP-17 are conserved molecules with no known function in neurons. Thus, understanding the neuronal function and mechanisms of action for these molecules will bring us significantly closer to the goal of understanding how to build a synapse, and the ultimate goal of pharmacologically manipulating this process for maximum therapeutic impact.
Neurodegenerative disease and trauma to the CNS are major public health issues that afflict more than 50 million Americans yearly. This research program will lay the foundation for broad based and preventative therapies that will reduce the physical, emotional and financial impacts of these diseases on the public.
|Tulgren, Erik D; Turgeon, Shane M; Opperman, Karla J et al. (2014) The Nesprin family member ANC-1 regulates synapse formation and axon termination by functioning in a pathway with RPM-1 and ?-Catenin. PLoS Genet 10:e1004481|
|Baker, Scott T; Opperman, Karla J; Tulgren, Erik D et al. (2014) RPM-1 uses both ubiquitin ligase and phosphatase-based mechanisms to regulate DLK-1 during neuronal development. PLoS Genet 10:e1004297|
|Opperman, Karla J; Grill, Brock (2014) RPM-1 is localized to distinct subcellular compartments and regulates axon length in GABAergic motor neurons. Neural Dev 9:10|
|Grill, Brock; Chen, Lizhen; Tulgren, Erik D et al. (2012) RAE-1, a novel PHR binding protein, is required for axon termination and synapse formation in Caenorhabditis elegans. J Neurosci 32:2628-36|