Genetic mutations that severely diminish the activity of
aspartoacylase (ASPA) result in the fatal brain dysmyelinating disorder,
Canavan disease. There is no effective treatment. ASPA produces free
acetate from the concentrated brain metabolite,
N-acetylaspartate (NAA). Because
acetyl coenzyme A is a key building block for
lipid synthesis, we postulated that the inability to catabolize NAA leads to a brain
acetate deficiency during a critical period of CNS development, impairing myelination and possibly other aspects of brain development. We tested the hypothesis that
acetate supplementation during postnatal myelination would ameliorate the severe phenotype associated with
ASPA deficiency using the
tremor rat model of
Canavan disease. Glyceryltriacetate (GTA) was administered orally to
tremor rats starting 7 days after birth, and was continued in food and water after weaning. Motor function, myelin
lipids, and brain vacuolation were analyzed in GTA-treated and untreated
tremor rats. Significant improvements were observed in motor performance and myelin
galactocerebroside content in
tremor rats treated with GTA. Further, brain vacuolation was modestly reduced, and these reductions were positively correlated with improved motor performance. We also examined the expression of the
acetyl coenzyme A synthesizing
enzyme acetyl coenzyme A synthase 1 and found upregulation of expression in
tremor rats, with a return to near normal expression levels in GTA-treated
tremor rats. These results confirm the critical role played by NAA-derived
acetate in brain myelination and development, and demonstrate the potential usefulness of
acetate therapy for the treatment of
Canavan disease.