A MODEL OF HUMAN GANGLIOSIDOSIS

点击翻译按钮获取中文摘要

Lysosomal storage diseases are 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 disease, including the gangliosidoses. Although much has been learned about specific defects 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 significantly retards progress on development of therapeutic strategies. 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 gangliosidoses. We hypothesize that these changes are manifested by altered calcium homeostasis resulting in disruption of calcium- dependent functions, including neurotransmission. 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. Our hypothesis that altered calcium homeostasis is the central pathogenic effect responsible for neuronal dysfunction in these diseases provides, for the first time, the necessary rationale for development of drug therapy.