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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurology B Subcommittee 1 (NEUB)
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Albert Einstein College of Medicine
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United States
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Walkley, S U; Thrall, M A; Haskins, M E et al. (2005) Abnormal neuronal metabolism and storage in mucopolysaccharidosis type VI (Maroteaux-Lamy) disease. Neuropathol Appl Neurobiol 31:536-44
Walkley, S U; Zervas, M; Wiseman, S (2000) Gangliosides as modulators of dendritogenesis in normal and storage disease-affected pyramidal neurons. Cereb Cortex 10:1028-37
Walkley, S U; Siegel, D A; Dobrenis, K et al. (1998) GM2 ganglioside as a regulator of pyramidal neuron dendritogenesis. Ann N Y Acad Sci 845:188-99
Jolly, R D; Walkley, S U (1997) Lysosomal storage diseases of animals: an essay in comparative pathology. Vet Pathol 34:527-48
March, P A; Thrall, M A; Brown, D E et al. (1997) GABAergic neuroaxonal dystrophy and other cytopathological alterations in feline Niemann-Pick disease type C. Acta Neuropathol (Berl) 94:164-72
Goodman, L A; Walkley, S U (1996) Elevated GM2 ganglioside is associated with dendritic proliferation in normal developing neocortex. Brain Res Dev Brain Res 93:162-71
Brown, D E; Thrall, M A; Walkley, S U et al. (1996) Metabolic abnormalities in feline Niemann-Pick type C heterozygotes. J Inherit Metab Dis 19:319-30
Walkley, S U; Siegel, D A; Dobrenis, K (1995) GM2 ganglioside and pyramidal neuron dendritogenesis. Neurochem Res 20:1287-99
Walkley, S U (1995) Pyramidal neurons with ectopic dendrites in storage diseases exhibit increased GM2 ganglioside immunoreactivity. Neuroscience 68:1027-35
Walkley, S U; Thrall, M A; Dobrenis, K et al. (1994) Bone marrow transplantation corrects the enzyme defect in neurons of the central nervous system in a lysosomal storage disease. Proc Natl Acad Sci U S A 91:2970-4

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