The concept that neuronal storage diseases are inherited defects in the lysosomal system of cells has shown substantial development in recent years. However, an understanding as to how this storage phenomenon actually leads to cellular dysfunction has been slower to develop. The discovery that morphological changes in neurons in ganglioside storage disease consist not only of cellular enlargement concomitant to storage, but also of highly specific alterations including aberrant neurite, meganeurite and associated synapse formation, has led to entirely new ways of characterizing these diseases. It is now apparent that such disorders can be viewed, not just as storage phenomena, but also as disorders in the production and regulation of neuronal surface membrane. Further, and perhaps of greater significance, the occurrence of renewed dendritogenesis and synaptogenesis on morphologically mature neurons prompts the view that a hallmark of these disorders is the formation of altered synaptic connections in select brain regions. The present study will fully explore these unusual phenomena using the biomedical resource of animal models of neuronal storage disease. Lesion studies in these models, combined with various manipulative and specialized morphological techniques, including the combined Golgi-EM method, will allow for determination of the source of aberrant synaptic input to neurite and meganeurite areas. Further, the recent development of the locoweed-induced Alpha-mannosidosis model and the discovery that this disorder is accompanied in the early stages by the same axon hillock spine growth as seen in the gangliosidoses (and suggestive of similar aberrant synapse formation), offers a unique opportunity to study the initiation, development, and modifiability of these aberrant phenomena. These studies on the pathobiology of neuronal storage disease can be expected to generate new and important data concerning basic aspects of neurobiology, particularly those related to dendritogenesis and synaptogenesis. Additionally, these studies will increase our understanding of the pathogenesis of these unusual disorders and give insight into possible boundary conditions for any future treatment regimens designed to alleviate such conditions in humans.
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