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

https://doi.org/10.1016/j.mce.2006.03.016Get rights and content

Abstract

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. Our hypothesis is that ASPA actively participates in myelin synthesis by providing NAA-derived acetate for acetyl CoA synthesis, which in turn is used for synthesis of the lipid portion of myelin. Consequently, CD results from defective myelin synthesis due to a deficiency in the supply of the NAA-derived acetate. The demonstration of the selective localization of ASPA in oligodendrocytes in the central nervous system (CNS) is consistent with the acetate deficiency hypothesis of CD. We have tested this hypothesis by determining acetate levels and studying myelin lipid synthesis in the ASPA gene knockout model of CD, and the results provided the first direct evidence in support of this hypothesis. Acetate supplementation therapy is proposed as a simple and inexpensive therapeutic approach to this fatal disease, and progress in our preclinical efforts toward this goal is presented.

Section snippets

NAA is an acetate carrier during CNS development

The connections between ASPA gene mutations and the loss of deacetylase activity are both well established in CD, and yet the specific connection between ASPA deficiency and the failure of proper CNS development and axonal myelination remains unclear (Matalon et al., 1995). In addition, the precise roles that NAA plays in the development of the CNS, and its proper functioning, remain a matter of study.

There are several hypotheses proposed to explain the role of NAA in the CNS. One of them

Recent findings from ASPA (−/−) mice

Reports on incorporation of the acetyl moiety of NAA into acetyl CoA and lipids during myelination, and other evidence that ASPA is associated with myelination did not shed light on the relative importance of this pathway for myelination. It was not clear if this was a salvage pathway for lipid synthesis, or a primary pathway. In most cell types, such as hepatocytes, the enzyme ATP-citrate lyase provides the acetyl groups for fatty acid synthesis. The extent of contribution of NAA–ASPA system

Preclinical efforts toward acetate supplementation therapy for CD

In view of the evidence presented above that brain acetate levels and myelin lipid synthesis are both significantly reduced in CD mice, then it follows that correcting the acetate deficit by acetate supplementation could provide a therapeutic approach for treating the dysmyelination in CD. In our preclinical efforts toward such a therapy for CD, we are currently examining glyceryl triacetate (GTA; Triacetin) and calcium acetate as potential exogenous acetate sources for delivering acetate to

Final comments

Presently it remains a matter of controversy what pathological mechanisms are primary in CD, and which are less critical. It seems clear now that an acetate deficiency caused by dysfunction in a specific enzyme in oligodendrocytes has an etiological role in CD. It is also possible that osmotic dysregulation in the CNS is mediated by excessive extracellular NAA concentrations, and that high NAA concentrations lead to seizures, which further contribute to the pathogenesis. However, we should not

Acknowledgements

This work was supported by NIH grants RO1 NS39387 and R21 MH 068341 and Samueli Institute for Information Biology grant GS170 ON to M.A.A.N.

References (48)

  • M.A. Namboodiri et al.

    Murine aspartoacylase: cloning, expression and comparison with the human enzyme

    Brain Res. Mol. Brain Res.

    (2000)
  • M. Tranberg et al.

    NMDA-receptor mediated efflux of N-acetylaspartate: physiological and/or pathological importance?

    Neurochem. Int.

    (2004)
  • A. Bach et al.

    Fats with short and medium chains. Physiological, biochemical, nutritional, and therapeutic aspects

    Ann. Nutr. Aliment.

    (1970)
  • P.B. Barker et al.

    Proton NMR spectroscopy of Canavan's disease

    Neuropediatrics

    (1992)
  • G. Bartalini et al.

    Biochemical diagnosis of Canavan disease

    Child. Nerv. Syst.

    (1992)
  • M.H. Baslow

    Brain N-acetylaspartate as a molecular water pump and its role in the etiology of Canavan disease: a mechanistic explanation

    J. Mol. Neurosci.

    (2003)
  • K.K. Bhakoo et al.

    Developmental and regional distribution of aspartoacylase in rat brain tissue

    J. Neurochem.

    (2001)
  • R. Burri et al.

    N-acetyl-l-aspartate is a major source of acetyl groups for lipid synthesis during rat brain development

    Dev. Neurosci.

    (1991)
  • G. Chakraborty et al.

    Intraneuronal N-acetylaspartate supplies acetyl groups for myelin lipid synthesis: evidence for myelin-associated aspartoacylase

    J. Neurochem.

    (2001)
  • A.F. D’Adamo et al.

    Acetyl transport mechanisms. Involvement of N-acetyl aspartic acid in de novo fatty acid biosynthesis in the developing rat brain

    Exp. Brain Res.

    (1968)
  • A.F. D’Adamo et al.

    N-acetyl-aspartate amidohydrolase: purification and properties

    J. Neurochem.

    (1977)
  • A.F. D’Adamo et al.

    The occurrence of N-acetylaspartate amidohydrolase (aminoacylase II) in the developing rat

    J. Neurochem.

    (1973)
  • A.F. D’Adamo et al.

    Acetate metabolism in the nervous system. N-acetyl-l-aspartic acid and the biosynthesis of brain lipids

    J. Neurochem.

    (1966)
  • P. Divry et al.

    Aspartoacylase deficiency and N-acetylaspartic aciduria in patients with Canavan disease

    Am. J. Med. Genet.

    (1989)
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