PATHOBIOLOGY OF NEURONAL STORAGE DISEASE

Project: Research project

Project Details

Description

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.
StatusFinished
Effective start/end date1/1/901/1/90

Funding

  • National Institute of Neurological Disorders and Stroke

ASJC

  • Neurology
  • Biological Psychiatry
  • Cellular and Molecular Neuroscience
  • Molecular Medicine
  • Developmental Neuroscience

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