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

Arun P, Madhavarao CN, Moffett JR, Hamilton K, Grunberg NE, Ariyannur PS, Gahl WA, Anikster Y, Mog S, Hallows WC, Denu JM, Namboodiri AM - J. Inherit. Metab. Dis. (2010)

Bottom Line: There is no effective treatment.Further, brain vacuolation was modestly reduced, and these reductions were positively correlated with improved motor performance.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy, Physiology and Genetics, Neuroscience Program and Molecular and Cell Biology Program, Uniformed Services University of the Health Sciences, Building C, Bethesda, MD 20814, USA.

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.

Show MeSH

Related in: MedlinePlus

AceCS1-immunoreactivity comparison between adult wild,type and GTA treated and untreated tremor rats: low magnification images (left column), higher magnification images (right column). AceCS1 immunoreactivity in the cortex of an adult control rat (a,b) shows expression predominantly in cell nuclei in all layers of cortex. In a representative untreated adult tremor rat (c,d), AceCS1 expression was moderately upregulated, including in oligodendrocytes in the corpus callosum (cc). In a representative adult GTA-treated tremor rat (e,f), AceCS1 expression was reduced relative to untreated tremor rats, and was similar to the expression levels in control animals. Bar (in f): 300 µm (a,c,e), 120 µm (b,d,f)
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2877317&req=5

Fig6: AceCS1-immunoreactivity comparison between adult wild,type and GTA treated and untreated tremor rats: low magnification images (left column), higher magnification images (right column). AceCS1 immunoreactivity in the cortex of an adult control rat (a,b) shows expression predominantly in cell nuclei in all layers of cortex. In a representative untreated adult tremor rat (c,d), AceCS1 expression was moderately upregulated, including in oligodendrocytes in the corpus callosum (cc). In a representative adult GTA-treated tremor rat (e,f), AceCS1 expression was reduced relative to untreated tremor rats, and was similar to the expression levels in control animals. Bar (in f): 300 µm (a,c,e), 120 µm (b,d,f)

Mentions: AceCS1 expression was upregulated in adult tremor rats as compared with controls (Figs. 6 and 7). AceCS1 was expressed moderately to strongly in some cellular nuclei in adult control rats, including neuronal and glial cell nuclei (Figs. 6a, b and 7a). In tremor rats, AceCS1 expression was substantially increased relative to control animals (Figs. 6c, d and 7b). GTA-treatment of tremor rats reduced AceCS1 expression relative to untreated tremor rats and returned expression levels closer to those observed in control rats (Figs. 6e, f and 7c). In brain areas where severe vacuolation was observed in tremor rats, GTA treatment modestly reduced the degree of vacuolation. The lateral hypothalamus is one forebrain area that exhibits substantial vacuolation in tremor rats (Fig. 8). In wild-type control rats, AceCS1 expression was present in scattered cell nuclei throughout this region (Fig. 8a). In untreated tremor rats, AceCS1 expression was upregulated, and extensive vacuolation was observed in the lateral hypothalamus (Fig. 8b). In GTA-treated tremor rats, AceCS1 expression was reduced to near control levels, and the degree of vacuolation was modestly reduced (Fig. 8c).Fig. 6


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

Arun P, Madhavarao CN, Moffett JR, Hamilton K, Grunberg NE, Ariyannur PS, Gahl WA, Anikster Y, Mog S, Hallows WC, Denu JM, Namboodiri AM - J. Inherit. Metab. Dis. (2010)

AceCS1-immunoreactivity comparison between adult wild,type and GTA treated and untreated tremor rats: low magnification images (left column), higher magnification images (right column). AceCS1 immunoreactivity in the cortex of an adult control rat (a,b) shows expression predominantly in cell nuclei in all layers of cortex. In a representative untreated adult tremor rat (c,d), AceCS1 expression was moderately upregulated, including in oligodendrocytes in the corpus callosum (cc). In a representative adult GTA-treated tremor rat (e,f), AceCS1 expression was reduced relative to untreated tremor rats, and was similar to the expression levels in control animals. Bar (in f): 300 µm (a,c,e), 120 µm (b,d,f)
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2877317&req=5

Fig6: AceCS1-immunoreactivity comparison between adult wild,type and GTA treated and untreated tremor rats: low magnification images (left column), higher magnification images (right column). AceCS1 immunoreactivity in the cortex of an adult control rat (a,b) shows expression predominantly in cell nuclei in all layers of cortex. In a representative untreated adult tremor rat (c,d), AceCS1 expression was moderately upregulated, including in oligodendrocytes in the corpus callosum (cc). In a representative adult GTA-treated tremor rat (e,f), AceCS1 expression was reduced relative to untreated tremor rats, and was similar to the expression levels in control animals. Bar (in f): 300 µm (a,c,e), 120 µm (b,d,f)
Mentions: AceCS1 expression was upregulated in adult tremor rats as compared with controls (Figs. 6 and 7). AceCS1 was expressed moderately to strongly in some cellular nuclei in adult control rats, including neuronal and glial cell nuclei (Figs. 6a, b and 7a). In tremor rats, AceCS1 expression was substantially increased relative to control animals (Figs. 6c, d and 7b). GTA-treatment of tremor rats reduced AceCS1 expression relative to untreated tremor rats and returned expression levels closer to those observed in control rats (Figs. 6e, f and 7c). In brain areas where severe vacuolation was observed in tremor rats, GTA treatment modestly reduced the degree of vacuolation. The lateral hypothalamus is one forebrain area that exhibits substantial vacuolation in tremor rats (Fig. 8). In wild-type control rats, AceCS1 expression was present in scattered cell nuclei throughout this region (Fig. 8a). In untreated tremor rats, AceCS1 expression was upregulated, and extensive vacuolation was observed in the lateral hypothalamus (Fig. 8b). In GTA-treated tremor rats, AceCS1 expression was reduced to near control levels, and the degree of vacuolation was modestly reduced (Fig. 8c).Fig. 6

Bottom Line: There is no effective treatment.Further, brain vacuolation was modestly reduced, and these reductions were positively correlated with improved motor performance.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy, Physiology and Genetics, Neuroscience Program and Molecular and Cell Biology Program, Uniformed Services University of the Health Sciences, Building C, Bethesda, MD 20814, USA.

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.

Show MeSH
Related in: MedlinePlus