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

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...

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Autores principales: Arun, Peethambaran, Madhavarao, Chikkathur N., Moffett, John R., Hamilton, Kristen, Grunberg, Neil E., Ariyannur, Prasanth S., Gahl, William A., Anikster, Yair, Mog, Steven, Hallows, William C., Denu, John M., Namboodiri, Aryan M. A.
Formato: Texto
Lenguaje:English
Publicado: Springer Netherlands 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2877317/
https://www.ncbi.nlm.nih.gov/pubmed/20464498
http://dx.doi.org/10.1007/s10545-010-9100-z
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author Arun, Peethambaran
Madhavarao, Chikkathur N.
Moffett, John R.
Hamilton, Kristen
Grunberg, Neil E.
Ariyannur, Prasanth S.
Gahl, William A.
Anikster, Yair
Mog, Steven
Hallows, William C.
Denu, John M.
Namboodiri, Aryan M. A.
author_facet Arun, Peethambaran
Madhavarao, Chikkathur N.
Moffett, John R.
Hamilton, Kristen
Grunberg, Neil E.
Ariyannur, Prasanth S.
Gahl, William A.
Anikster, Yair
Mog, Steven
Hallows, William C.
Denu, John M.
Namboodiri, Aryan M. A.
author_sort Arun, Peethambaran
collection PubMed
description 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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spelling pubmed-28773172010-06-10 Metabolic acetate therapy improves phenotype in the tremor rat model of Canavan disease Arun, Peethambaran Madhavarao, Chikkathur N. Moffett, John R. Hamilton, Kristen Grunberg, Neil E. Ariyannur, Prasanth S. Gahl, William A. Anikster, Yair Mog, Steven Hallows, William C. Denu, John M. Namboodiri, Aryan M. A. J Inherit Metab Dis Original Article 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. Springer Netherlands 2010-05-13 2010 /pmc/articles/PMC2877317/ /pubmed/20464498 http://dx.doi.org/10.1007/s10545-010-9100-z Text en © The Author(s) 2010 https://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
spellingShingle Original Article
Arun, Peethambaran
Madhavarao, Chikkathur N.
Moffett, John R.
Hamilton, Kristen
Grunberg, Neil E.
Ariyannur, Prasanth S.
Gahl, William A.
Anikster, Yair
Mog, Steven
Hallows, William C.
Denu, John M.
Namboodiri, Aryan M. A.
Metabolic acetate therapy improves phenotype in the tremor rat model of Canavan disease
title Metabolic acetate therapy improves phenotype in the tremor rat model of Canavan disease
title_full Metabolic acetate therapy improves phenotype in the tremor rat model of Canavan disease
title_fullStr Metabolic acetate therapy improves phenotype in the tremor rat model of Canavan disease
title_full_unstemmed Metabolic acetate therapy improves phenotype in the tremor rat model of Canavan disease
title_short Metabolic acetate therapy improves phenotype in the tremor rat model of Canavan disease
title_sort metabolic acetate therapy improves phenotype in the tremor rat model of canavan disease
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2877317/
https://www.ncbi.nlm.nih.gov/pubmed/20464498
http://dx.doi.org/10.1007/s10545-010-9100-z
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