The neuronal storage disorders are inherited defects in specific lysosomal hydrolases and are characterized by profound neurobehavioral deterioration and death. Although significant progress has been made in determining the specific enzymatic defects responsible for individual diseases, little is understood as to the ways in which resulting metabolic derrangements precipitate altered brain function. The discovery that storage disorders are characterized by neuron type-specific ectopic dendrite growth and new synapse formation, occurring well after the usual phase of dendritogenesis in normal nervous systems, has opened a new chapter in the study of these disorders. Fully understanding the causes and consequences of these alterations in neuronal connectivity may offer important clues to those factors underlying the process of synapse development and maintenance in normal nervous systems. Pursuant of this understanding, a series of experiments designed to explore two central hypotheses on the pathobiology of neuronal storage disease will be carried out. These hypotheses relate to (i) the source(s), functional consequence(s), and modifiability of the observed, altered synaptic connectivity, and (ii) the possible role of gangliosides in the induction of ectopic neurite (i.e., dendrite) growth. Immunocytochemical studies directed at specific neurotransmitters and a lectin-based anterograde transport method, in combination with Golgi staining and EM, will be employed to evaluate three specific, hypothesized changes in neuronal connectivity within cerebral cortex. These concern the intrinsic GABAergic system, and the intracortical distribution of cholinergic and thalamocortical afferents. Biochemical analyses and immunocytochemical studies with anti-ganglioside antibodies will be used to explore the hypothesized role of gangliosides in inducing ectopic neuritogenesis. A key element in these studies will be the availability of well characterized, biologically equivalent diseases in animals. The present study makes use of several inherited models of the gangliosidoses and of alpha- mannosidosis, and to a remarkable phenocopy of the latter as induced (reversibly) by a plant-derived alpha-mannosidase inhibitor (swainsonine). Taken as a whole, these studies can be expected to generate important new data on the phenomena of ectopic dendrite growth and new synapse formation in neuronal storage disorders, and to better relate these changes to events in the normal nervous system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS018804-06
Application #
3398847
Study Section
Neurology B Subcommittee 1 (NEUB)
Project Start
1983-07-01
Project End
1990-03-31
Budget Start
1989-04-01
Budget End
1990-03-31
Support Year
6
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461
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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