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William Mobley

Chair, Neurosciences, UC San Diego Distinguished Professor, Neurosciences, UC San Diego

Dr. Mobley’s research focuses on the neurobiology of neurotrophic factor actions and signaling and on the hypothesis that dysfunction of such signaling mechanisms contributes to neuronal dysfunction in developmental and age-related disorders of the nervous system. His emphasis on the neurobiology of Down syndrome has brought new insights into the disease, including possible treatments. He has also done pioneering work on the neurobiology of Alzheimer’s Disease (AD) using a mouse model of Down syndrome (DS). These studies were based on the observation that virtually all adults with Down syndrome develop the pathology of Alzheimer’s disease by the age of 50. This knowledge paved the way for Dr. Mobley’s ongoing studies of AD in experimental models.
Dr. Mobley’s laboratory has pursued two major themes. The first is the biology and signaling of neurotrophic factors. The second, propelled by the first, is the pathogenesis of developmental and age-related neurodegeneration in DS and AD. The Mobley Laboratory has made many important contributions to neuroscience investigation, all of which relate to the biology of neurotrophic factors or to the pathogenesis of DS. Three of these will be summarized here.

The first contribution, made in studies on nerve growth factor (NGF), was the demonstration that a neurotrophic factor acts in the central nervous system (CNS). Indeed, the lab is credited with having been among the very first to demonstrate this and to show that neurotrophic factors play similar roles in the CNS as in the Peripheral Nervous System (PNS). This contribution helped drive the search for other CNS neurotrophic factors, a search that defined the existence of many families of such factors. His lab was also among the first to point to a potential role for neurotrophic factors in the pathogenesis of neurodegeneration, a theme many labs have taken up and has prompted many attempts to treat patients with such disorders.

The second was the discovery of the “signaling endosome,” the organelle through which NGF and other neurotrophic factors signal retrogradely in axons from targets. The isolation and characterization of the signaling endosome provided an important new vista on the cellular basis of signaling, making it clear how signals could be sent with high fidelity for many hours over long distances. This work stimulated others to focus on the biological significance of the spatial localization of signaling in neurons and other cells. In recent work, the Mobley Laboratory has engaged in single molecule studies to decipher in detail how the signaling endosome is created and how it enables the matching of targets of innervation with their presynaptic inputs.

The third contribution involves the pathogenesis of developmental and age-related cognitive deficits in people with DS. The Mobley laboratory has played a central role in defining the neurobiology of DS. It has shown that genetic dissection, in parallel with studies of mechanism, can be used to decipher the basis for cognitive phenotypes and for identifying potential therapeutic targets. The laboratory was the first to show that even in the context of a complex genetic disorder a single gene for Amyloid Precursor Protein (APP) plays a conspicuous role in age-related pathogenesis. The gene for APP, and the endosomal dysregulation that occurs as a result of increased expression of this gene, are now potential targets for treating age-related neurodegeneration of hippocampal afferents. Another success has been in defining dysregulation of inhibitory neurotransmission, which led to defining both GABA A and B receptors and inwardly rectifying potassium channels downstream from GABA B receptors, as playing an important role in developmental events. The gene(s) that are critical for this aspect of pathogenesis are the topic of continuing studies.

To date, Dr. Mobley has published almost 150 research articles and reviews in peer reviewed journals. Publications appear in high quality journals, such J. Neuroscience, Neurobiol Dis., and J. Comp Neurol. In addition, Dr. Mobley is co-editor of one book and has contributed to 13 books or book chapters.