Steven U. Walkley

Pathobiology and Treatment of Lysosomal Disorders of Brain

The research interests of my laboratory are concerned with analysis of pathogenic cascades and development of therapeutic strategies for genetic disorders of the endosomal-lysosomal system known as neuronal storage diseases. Disorders include Tay-Sachs, Hurler, Sanfilippo, Niemann-Pick, Batten, and other related conditions, all of which are characterized by insidious onset and progression of neurological dysfunction, including mental retardation, following an initial period of normal development. Primary proteins implicated in storage diseases include not only lysosomal hydrolases but also soluble and membrane-associated proteins often of unknown function. Animal models of storage diseases include both spontaneous conditions in a variety of species and gene knockout models in mice, both of which are used extensively in our studies. Neurons affected by storage diseases often display remarkable features, including growth of ectopic dendrites and altered synaptic connectivity, formation of axonal defects, and selective vulnerability to premature death. Our studies are focused on the link between the primary protein defect and the abnormal accumulation of substrate (gangliosides, glycosaminoglycans, cholesterol, and so forth) and with subsequent induced changes in trafficking and signaling events within affected neurons. Therapeutic strategies include attempts to replace missing proteins through cell-mediated approaches (e.g., bone marrow transplantation) and to reduce storage pharmacologically with inhibitors of substrate synthesis (substrate reduction therapy), both of which have shown promise in specific types of storage disorders.

 

Selected Publications