PATHOBIOLOGY OF NEURONAL STORAGE DISEASE

The neuronal storage disorders result from inherited defects in specific lysosomal hydrolases and are characterized by an array of neurological symptoms including profound mental retardation/dementia, motor system derangements, sensory deficits such as blindness or deafness, and seizures. Such disease most often affect children and are invariably fatal. Although significant progress has been made in understanding the molecular genetics of these diseases and in determining the specific enzymatic defects responsible for individual diseases, little is presently understood as to the ways in which the resulting metabolic derangements generate altered brain function. The discovery that certain neuronal storage diseases are characterized y ectopic growth of dendrites in select neuronal populations, and more recently, that GABAergic neurons are predominately affected by the neuroaxonal dystrophy previously believed to occur non-specifically in many types of neurons, have opened new chapters in the study of these diseases. Fully understanding the causes and consequences of both phenomena will likely offer important insights into the regulation of dendrite growth and maintenance of axonal integrity in normal nervous systems, and will contribute important information about the possible reversibility of disease-induced alterations in brain following metabolic correction of the directed at these cytopathologic events characterizing storage disease. These hypotheses relate to (i) the possible association between ectopic dendritogenesis and mental retardation, (ii) the role of abnormalities in ganglioside metabolism in inducing new dendrite growth, and (iii) the possible association between axonal spheroid formation (neuroaxonal dystrophy) occurring predominately in GABAergic neurons and the motor system derangements and seizure tendencies which characterize many of these disorders. Immunocytochemical procedures at the light and electron microscopic levels will be applied to the study of GABAergic neurons and to the subcellular localization of gangliosides in storage diseases. Anterograde lectin transport studies will be directed at determining sources of synaptic input onto ectopic dendrites. Specific antagonists to NMDA receptors will be used to test the possible relationship between activation of these receptors and regulation of dendrite growth on pyramidal neurons. A key element in most of these studies will be the availability of inherited and induced models of neuronal storage disorders which are near-exact replicas of these diseases in children. The use of swainsonine, a reversible alpha-mannosidase inhibitor, will allow for the induction of a neuronal storage disease, alpha-mannosidosis, which can be metabolically normalized following removal of the inhibitor. Collaborative studies directed at bone marrow transplants in an inherited model with the same disease offer the opportunity for detailed analysis of disease reversibility. Taken as a whole, these studies can be expected to generate important new data on the phenomena of ectopic dendritogenesis and neuroaxonal dystrophy as they occur in storage disorders, and better relate these changes to cellular processes in normal nervous systems.