Acetate Deficiency Hypothesis Of Cd

Despite the established connection between mutations in the gene for ASPA in CD, and the lost capacity to deacetylate NAA, the specific connection between ASPA

deficiency and the failure of proper CNS development, and axonal myelination remains unclear.9,26 In addition, the precise roles that NAA plays in the development of the CNS, and its proper functioning, remain a matter of study. A number of different hypotheses have been proposed for the various roles played by NAA in the nervous system. The high concentration of NAA in the brain, its lack of known actions on neurons or glia, and its high concentration gradient from neurons to the extracellular space have led to the proposal that NAA is an organic osmolyte which removes excess water from neurons by acting as a molecular water pump.27 In this regard it has been proposed that excess NAA leads to osmotic dysregulation, or has other cytotoxic effects which are responsible for the pathology observed in CD patients.28,29

Another theory about the role of NAA for which there is mounting evidence is that NAA is essential for lipid synthesis and myelination in the CNS, especially during the period of peak, postnatal myelination that occurs in the CNS. In 1987, Hagenfeldt and colleagues proposed that the dismyelination observed in the brains of Canavan disease patients was due to the failure of NAA to act as an acetate carrier from mitochondria to the cytosol, thus impairing lipogenesis.15 The evidence in favor of this theory include the facts that the levels of NAA, ASPA and Asp-NAT rise with a temporal course which is highly similar to the time-course of myelin protein synthesis.30'31 Further, it has been shown that NAA contributes acetyl groups for the synthesis of lipids, which in turn are incorporated into myelin.32,33 Finally, radiolabeled NAA is transported down optic nerve axons and is incorporated into their ensheathing myelin lipids.34 Based on these and other observations we hypothesize that mutations in the gene encoding ASPA result in a deficiency in the supply of NAA-derived acetate, which in turn results in decreased synthesis of myelin-related fatty acids and lipids. We propose that it is this lipogenic deficiency that compromises CNS myelination, impairs CNS development, and ultimately results in the white matter degeneration observed in CD.35,36 We have recently tested the acetate deficiency hypothesis in the mouse model of CD by studying myelin lipid synthesis using the tritiated water incorporation method. The results showed significant decreases in 6 classes of newly synthesized myelin-associated lipids in the brains of these mice at the time of peak postnatal CNS myelination. Furthermore, brain acetate levels decreased by about 80% in CD mice, whereas acetate levels in the liver and kidney remained unchanged. These results demonstrate that myelin lipid synthesis is significantly compromised in CD, and provide the first direct evidence that defective myelin synthesis, resulting from a deficiency of NAA-supplied acetate, is involved in the pathogenesis of CD. These issues are discussed in detail in the following sections.

0 0

Post a comment