Project: Research project

Project Details


Batten's disease is an inherited neurological disorder affecting humans
and also has been documented in a variety of animal species including
dogs and sheep. Individuals with this disorder are characterized by
normal appearance at birth, followed by insidiously progressive
neurological deterioration including retarded mental development and/or
dementia, blindness, movement disorders, and seizures. Death is the in-
evitable outcome as no treatment is currently available. Only recently
has research progress begun to clarify the metabolic basis for this
disease in that massive storage of a single protein (subunit c of
mitochondrial ATP-synthase) has been established. This finding suggests
that Batten's disease is a proteolipid proteinosis, but the primary
enzyme defect awaits determination. Furthermore, changes in brain
structure and function set in motion by the primary metabolic defect and
that lead to the devastating neurological symptoms also are poorly
understood. Our goal in these studies is to use a well documented animal
model of Batten's disease, canine neuronal ceroid lipofuscinosis, to
explore mechanisms of pathogenesis. We have proposed two alternative
hypotheses to explain onset and progression of neuronal dysfunction.
Based on the observation that cortical GABAergic neurons contain more
mitochondria than other cortical neurons, coupled with identification of
a mitochondrial enzyme as the major storage product in this disease, we
propose that GABAergic neurons are inherently more susceptible to the
primary metabolic defect (Hypothesis I). According to this view, early
GABAergic cell loss would be predicted to precede pyramidal cell loss,
but the ensuing loss of inhibitory function would later accelerate
pyramidal cell dysfunction. Alternatively, brain dysfunction in Batten's
disease may be due to the same mechanisms believed critical in neuronal
storage diseases known to be caused by lysosomal hydrolase defects
(Hypothesis II). In these cases ectopic dendrites and associated
synaptic connections, axonal spheroids in GABAergic neurons, and
alterations in second messenger systems are believed linked to specific
aspects of brain dysfunction. We propose to use state-of-the-art
electrophysiologic and morphologic techniques to explore these
hypotheses. A greater understanding of the mechanisms of brain
dysfunction in Batten's e anticipated to give insight not only into the
primary metabolic defect in brain, but also into possible ways to treat
and/or ameliorate clinical symptoms.
Effective start/end date9/7/928/31/96


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


  • Clinical Neurology
  • Neurology


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