A MODEL OF HUMAN GANGLIOSIDOSIS

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Lysosomal storage diseases comprise a well delineated subset of inherited metabolic disorders with defective lysosomal catabolism. Severe, progressive central nervous system (CNS) dysfunction is the most apparent and clinically significant consequence of many of these diseases, including the gangliosidoses. Although much has been learned about specific errors in lysosomal biochemistry associated with these diseases, the underlying pathogenetic mechanisms responsible for CNS dysfunction remain very poorly understood. Early progress in revealing specific lysosomal enzyme deficiencies in these diseases raised optimism that corrective therapy could be developed. Unfortunately, little progress has been made toward implementation of promising therapeutic strategies. In fact, the current void in understanding basic pathogenetic events impacts significantly on development of therapeutic strategies, since it is not known if CNS function will be restored following correction of lysosomal catabolism. This project will exploit well characterized animal models of the gangliosidoses to probe crucial questions involving pathogenesis and therapy of lysosomal storage diseases. Our studies demonstrate major alterations in synaptic membrane composition induced by defective ganglioside catabolism in feline Gm1 gangliosidosis. We hypothesize that these changes are manifested functionally by altered synaptic transmission, with major effects on Ca++ dependent mechanisms, and morphologically by aberrant neuronal membrane growth induced by excess cyclic AMP. Our proposed studies will pursue this exciting hypothesis by systematically exploring the functional properties of neuronal membrane in the feline gangliosidoses. There is some reason for optimism about the possible application of bone marrow transplantation (BMT) therapy for lysosomal storage diseases. However, it is crucial that comprehensive studies be performed in valid experimental animal models which will rigorously test biochemical and morphological changes in visceral organs and CNS following BMT. Therefore, we propose to perform systematic studies focused on evaluating BMT therapy for lysosomal storage diseases employing cats with Gm1 gangliosidosis.