Canavan disease and the role of N-acetylaspartate in myelin synthesis
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.
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2019, Molecular Genetics and MetabolismCitation Excerpt :Canavan disease (OMIM#271900) is another inherited metabolic disorder, which is caused by defective catabolism of the N-acetyl-L-aspartic acid (NAA). Canavan disease is a fatal autosomal-recessive neurodegenerative disease characterized by compromised central nervous system (CNS) development, defects in myelination, astrocyte hypertrophy, and deformed mitochondria [16–18]. Patients exhibit elevated NAA levels due to the deficiency of the aspartoacylase (ASPA) enzyme, responsible for the degradation of NAA into acetate and aspartate [17,19].
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