PATHOBIOLOGY OF NEURONAL STORAGE DISEASE

Project: Research project

Project Details

Description

The neuronal storage disorders result from inherited defects in specific
lysosomal hydrolases and are characterized by an array of neurological
symptoms including profound mental retardation/dementia, motor system
derangements, sensory deficits such as blindness or deafness, and seizures.
Such disease most often affect children and are invariably fatal. Although
significant progress has been made in understanding the molecular genetics
of these diseases and in determining the specific enzymatic defects
responsible for individual diseases, little is presently understood as to
the ways in which the resulting metabolic derangements generate altered
brain function. The discovery that certain neuronal storage diseases are
characterized y ectopic growth of dendrites in select neuronal populations,
and more recently, that GABAergic neurons are predominately affected by the
neuroaxonal dystrophy previously believed to occur non-specifically in many
types of neurons, have opened new chapters in the study of these diseases.
Fully understanding the causes and consequences of both phenomena will
likely offer important insights into the regulation of dendrite growth and
maintenance of axonal integrity in normal nervous systems, and will
contribute important information about the possible reversibility of
disease-induced alterations in brain following metabolic correction of the
directed at these cytopathologic events characterizing storage disease.
These hypotheses relate to (i) the possible association between ectopic
dendritogenesis and mental retardation, (ii) the role of abnormalities in
ganglioside metabolism in inducing new dendrite growth, and (iii) the
possible association between axonal spheroid formation (neuroaxonal
dystrophy) occurring predominately in GABAergic neurons and the motor
system derangements and seizure tendencies which characterize many of these
disorders. Immunocytochemical procedures at the light and electron
microscopic levels will be applied to the study of GABAergic neurons and to
the subcellular localization of gangliosides in storage diseases.
Anterograde lectin transport studies will be directed at determining
sources of synaptic input onto ectopic dendrites. Specific antagonists to
NMDA receptors will be used to test the possible relationship between
activation of these receptors and regulation of dendrite growth on
pyramidal neurons. A key element in most of these studies will be the
availability of inherited and induced models of neuronal storage disorders
which are near-exact replicas of these diseases in children. The use of
swainsonine, a reversible alpha-mannosidase inhibitor, will allow for the
induction of a neuronal storage disease, alpha-mannosidosis, which can be
metabolically normalized following removal of the inhibitor. Collaborative
studies directed at bone marrow transplants in an inherited model with the
same disease offer the opportunity for detailed analysis of disease
reversibility. Taken as a whole, these studies can be expected to generate
important new data on the phenomena of ectopic dendritogenesis and
neuroaxonal dystrophy as they occur in storage disorders, and better relate
these changes to cellular processes in normal nervous systems.
StatusFinished
Effective start/end date1/1/908/31/96

Funding

  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke

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