Canavan disease and the role of N-acetylaspartate in myelin synthesis

@article{Namboodiri2006CanavanDA,
  title={Canavan disease and the role of N-acetylaspartate in myelin synthesis},
  author={A. Namboodiri and Arun Peethambaran and Raji Mathew and Prasanth A. Sambhu and Jeremy R. Hershfield and J. Moffett and C. N. Madhavarao},
  journal={Molecular and Cellular Endocrinology},
  year={2006},
  volume={252},
  pages={216-223}
}
Canavan disease (CD) is an autosomal-recessive neurodegenerative disorder caused by inactivation of the enzyme aspartoacylase (ASPA, EC 3.5.1.15) due to mutations. ASPA releases acetate by deacetylation of N-acetylaspartate (NAA), a highly abundant amino acid derivative in the central nervous system. CD results in spongiform degeneration of the brain and severe psychomotor retardation, and the affected children usually die by the age of 10. The pathogenesis of CD remains a matter of inquiry… Expand
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TLDR
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TLDR
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TLDR
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TLDR
In these two sibs, urinary concentration of NAA appears to correlate inversely to symptom severity and CD progression, and a novel missense mutation causing a CD phenotype with severe clinical characteristics is found. Expand
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TLDR
The results indicate that N‐acetylaspartic acid promotes oxidative stress by stimulating lipid peroxidation, protein oxidation and by decreasing non‐enzymatic antioxidant defenses in rat brain. Expand
N-Acetylaspartate and N-acetylaspartylglutamate
TLDR
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Intracerebroventricular administration of N-acetylaspartic acid impairs antioxidant defenses and promotes protein oxidation in cerebral cortex of rats
TLDR
Results indicate that intracerebroventricular administration of NAA impairs antioxidant defenses and induces oxidative damage to proteins, which could be involved in the neurotoxicity of N AA accumulation in CD patients. Expand
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References

SHOWING 1-10 OF 47 REFERENCES
Defective N-acetylaspartate catabolism reduces brain acetate levels and myelin lipid synthesis in Canavan's disease.
TLDR
It is demonstrated that myelin lipid synthesis is significantly compromised in CD and direct evidence that defective myelin synthesis, resulting from a deficiency of NAA-derived acetate, is involved in the pathogenesis of CD is provided. Expand
Immunohistochemical localization of aspartoacylase in the rat central nervous system
TLDR
The predominant immunoreactivity in oligodendrocytes is consistent with the proposed role of ASPA in myelination, supporting the case for acetate supplementation as an immediate and inexpensive therapy for infants diagnosed with CD. Expand
Restoration of aspartoacylase activity in CNS neurons does not ameliorate motor deficits and demyelination in a model of Canavan disease.
TLDR
The data suggest that NAA-mediated neuronal hyperexcitation but not oligodendrocyte dysfunction can be compensated for by neuronal ASPA expression, as well as reducing NAA levels, along with a rescue of the seizure phenotype. Expand
Aspartoacylase deficiency and N-acetylaspartic aciduria in patients with Canavan disease.
Brain N-acetylaspartate as a molecular water pump and its role in the etiology of canavan disease
  • M. Baslow
  • Biology, Medicine
  • Journal of Molecular Neuroscience
  • 2007
TLDR
Although NAA may perform several functions in the CNS, an important role of NAA appears to be osmoregulatory, and an osmotic-hydrostatic mechanism for the etiology of the CD phenotype is proposed. Expand
Developmental increase of aspartoacylase in oligodendrocytes parallels CNS myelination.
TLDR
The developmental expression pattern of aspartoacylase gene in the postnatal brain closely parallels myelination in the CNS, indicating that the role of N-acetylaspartate in myelin synthesis is restricted to the CNS and providing additional support for the acetate deficiency hypothesis of Canavan disease. Expand
Aspartoacylase is restricted primarily to myelin synthesizing cells in the CNS: therapeutic implications for Canavan disease.
TLDR
Findings provide strong additional support for insufficient myelin synthesis as the pathogenic basis of Canavan disease and make a compelling case for acetate supplementation as a simple and noninvasive therapy for this fatal disease with no treatment. Expand
Progress toward Acetate Supplementation Therapy for Canavan Disease: Glyceryl Triacetate Administration Increases Acetate, but Not N-Acetylaspartate, Levels in Brain
TLDR
GTA is proposed as a potential candidate for use in acetate supplementation therapy for CD because the dose of GTA required to maintain similarly elevated acetate levels in the brain increased with age and GTA was significantly more effective as an acetate source than calcium acetate. Expand
Spongy degeneration of the brain, Canavan disease: biochemical and molecular findings.
TLDR
The carrier frequency for the two common mutations among Ashkenazi Jews was found to be surprisingly high, 1:37, which allowed for accurate diagnosis of Canavan disease, while prior to that, a brain biopsy was needed. Expand
Intraneuronal N‐acetylaspartate supplies acetyl groups for myelin lipid synthesis: evidence for myelin‐associated aspartoacylase
TLDR
It is demonstrated that within white matter, aspartoacylase is an integral component of the myelin sheath where it is ideally situated to produce acetyl groups for synthesis of myelin lipids. Expand
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