Our nervous system is the primary organ by which we sense, interpret, remember, and respond to the outside world and to our own internal physiology. This elaborate system of neurons functions as a communication network, with vast arrays of chemical and electrical synapses between individual neuronal cells. The nervous system also interfaces with other tissues of the body, either directly (e.g., neuromuscular junctions at skeletal muscles) or indirectly (e.g., the release of hormones, biogenic amine neurotransmitters, and neuropeptides into the blood stream), to regulate physiology and behavior, as well as maintain overall body homeostasis. Unlike many bodily tissues, the nervous system is largely incapable of replacing damaged cells once development is complete, making it susceptible to traumatic injury and age-associated decline. The high energy demands of electrochemical signaling, combined with the inability to store energy in the form of glycogen reserves, makes neurons highly dependent on oxygen, oxidative phosphorylation, and mitochondria. The nervous system has evolved multiple mechanisms to maximize mitochondrial function and prevent damage from acute oxygen starvation. Indeed, the underlying etiology of many neurological disorders and diseases, including ischemic stroke, Parkinson’s Disease, and Alzheimer’s Disease, are due to defects in one or more of these key neurophysiological processes. A more complete understanding of these processes will facilitate better diagnosis and treatment of multiple neurological disorders.
We focus on understanding three areas of neurophysiology. First, we are interested in understanding how the transport and dynamics of mitochondria are mediated along axons and dendrites, as well as at synapses. Second, we are interested in understanding how neurons, synapses, and neuronal mitochondria respond to hypoxic stress (e.g., ischemic stroke). Finally, we are interested in understanding the function of the Ubiquitin Proteasome System (UPS) and its role in cellular aging, including the function of the UPS in neurons, as well as how neurons can regulate the UPS and proteostasis in distal tissues.
We use C. elegans to study these areas of neurophysiology because the nematode has a simple nervous system, which is easily visualized through its transparent body, allowing us to observe mitochondria and other structures within neurons in an intact and behaving animal. My lab has used the rich genetic and genomic tools of this organism, and both forward and reverse genetic approaches, to identify multiple genes that function in mitochondrial, hypoxic stress, and UPS biology. The genes we have identified have human equivalents that seem to be playing similar or identical roles in the human brain, suggesting that our findings are likely to be applicable to human health.