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Open Access 01-06-2010 | Original Article

Metabolic acetate therapy improves phenotype in the tremor rat model of Canavan disease

Authors: Peethambaran Arun, Chikkathur N. Madhavarao, John R. Moffett, Kristen Hamilton, Neil E. Grunberg, Prasanth S. Ariyannur, William A. Gahl, Yair Anikster, Steven Mog, William C. Hallows, John M. Denu, Aryan M. A. Namboodiri

Published in: Journal of Inherited Metabolic Disease | Issue 3/2010

Abstract

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.

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Title: Metabolic acetate therapy improves phenotype in the tremor rat model of Canavan disease
Authors: Peethambaran Arun
Chikkathur N. Madhavarao
John R. Moffett
Kristen Hamilton
Neil E. Grunberg
Prasanth S. Ariyannur
William A. Gahl
Yair Anikster
Steven Mog
William C. Hallows
John M. Denu
Aryan M. A. Namboodiri
Publication date: 01-06-2010
Publisher: Springer Netherlands
Published in: Journal of Inherited Metabolic Disease / Issue 3/2010
Print ISSN: 0141-8955
Electronic ISSN: 1573-2665
DOI: https://doi.org/10.1007/s10545-010-9100-z

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