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Canavan Disease
Canavan disease is the
only identified genetic disorder that is caused by a defect in the
processing of a metabolite that is produced exclusively in the brain. The enzyme
aspartoacylase plays a critical role in brain metabolism, the deacetylation
of N-acetylaspartic acid (NAA) to produce acetate and aspartate, and
appears to be the only enzyme in brain that can effectively metabolize NAA. A deficiency in aspartoacylase activity
has been implicated in the abnormally high NAA levels found in these
patients, thus establishing aspartoacylase as the biochemical defect in
Canavan disease.
While the precise role
of NAA has not been defined, it has been conclusively demonstrated that for
optimal health the concentration of this metabolite must be controlled
within a narrow range. This control
requires a balance between the activities of aspartate N-acetyltransferase
and aspartoacylase, the enzymes responsible for the synthesis and
degradation of NAA (scheme 1). Low
brain NAA levels are a hallmark of neuronal injury and death. A decrease in neuronal NAA concentration
has been observed in many neurodegenerative diseases, including epilepsy,
multiple sclerosis, myotrophic lateral sclerosis, and Alzheimer’s
disease. In contrast, an
accumulation of NAA in neurons is hypothesized to be the causative agent
for Canavan disease, a fatal, genetically transmitted neurodegenerative
disorder.
Scheme
I: Synthesis and Degradation of N-acetyl-l-Aspartate in Neurons
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Viola Research Group