Editors' ChoiceGene Therapy

Canavan disease: Can two wrongs make a right?

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Science Translational Medicine  08 Jul 2015:
Vol. 7, Issue 295, pp. 295ec115
DOI: 10.1126/scitranslmed.aac8103

N-acetyl-aspartate (NAA) comprises over 0.1% of the human brain by weight, making it one of the most abundant compounds in the central nervous system. The function of NAA is complex: In addition to a major role in myelin synthesis, NAA is also an osmolyte and molecular water pump. In the brain, NAA is made exclusively in the mitochondria of neurons and is sequestered inside the cell body, forming a large concentration gradient with the extracellular space. It is transported and taken up by glia, where it is used for myelin synthesis after hydrolysis by aspartoacylase (ASPA). NAA deficiency is associated with neurodegenerative and psychiatric diseases including Alzheimer's disease, whereas excess NAA is associated with a single disorder, Canavan disease (CD). Guo et al. now present evidence suggesting that a combination of ASPA deficiency and NAA synthase deficiency is sufficient to rescue the Canavan phenotype in mice.

CD is a rare pediatric leukodystrophy caused by a deficiency of ASPA. An even rarer disease was described in a single patient in 2001 who had a faulty NAA synthase gene (Nat8L) leading to a total absence of brain NAA. In a sense, Nat8L deficiency is the opposite of CD, but oddly enough, loss of Nat8L is also typified by hypomyelination, seizures, and developmental delay, though less severe than that observed in CD. The common feature in both disorders is a lack of readily available acetate for myelin synthesis. It is thought that dysmyelination in CD is due to inadequate acetyl-CoA in oligodendrocytes where ASPA is absent, as well as myelin destruction from osmotic effects due to excess NAA. In contrast, Nat8L deficiency is primarily a disorder of hypomyelination. The relative importance of different roles for NAA is an ongoing debate in terms of pathophysiology of CD and other brain disorders.

Guo et al. set out to test the hypothesis that osmotically active NAA is the main contributor to dysmyelination in CD, as opposed to the alternative hypothesis that deficiency of available acetyl-CoA in oligdendrocytes leads to hypomyelination. By cross-breeding nur7 transgenic mice lacking functional ASPA with Nat8L knockout mice, Guo et al. compared the case of abnormally high NAA in the setting of ASPA deficiency with abnormally low NAA in the setting of absent Nat8L. They found that CD pathology, with severe dysmyelination and impairment on rotorod testing, only occurred in the context of high NAA when Nat8L was present, and that the absence of NAA together with absence of ASPA alleviated symptoms of CD.

While the authors did not actually disprove the hypomyelination hypothesis of CD, this study helps to explain clinical findings in the unique human case of spontaneous deletion of Nat8L. Surprisingly, the authors found that the Nat8L knockout mouse had normal myelination, while the human case was severely affected with hypomyelination. The authors acknowledge that the phenotype of this mouse model was less severe than the human case and propose an explanation through better compensatory upregulation of citrate lyase, an alternative pathway for acetyl-CoA production.

The translational significance of this study is that it may be possible to develop inhibitors of NAA synthase for treatment of CD, similar to the substrate reduction approach using deoxynojirimycin in lysosomal storage diseases. In a complementary strategy of global NAA knockdown, a gene therapy clincial trial in CD patients using AAV carrying ASPA was reported in 2012, an approach which this paper appears to validate. Although not discussed by Guo et al. in their study, Nat8L knockout animals show increased D1 receptor expression in the striatum with a heighted response to metamphetamine and have been studied mainly in drug addiction experiments. Thus, humans lacking NAA synthase activity may be prone to behavioral disturbances and caution is warranted in broadly removing its action. Moreover, in vivo magnetic resonance spectroscopy studies have shown that NAA synthesis is down-regulated in CD by 60% compared with healthy individuals, but steady-state NAA levels remain high due to lack of ASPA. As a result, inhibitors may need to completely block NAA synthesis in order to be effective. Aside from its role in CD, Nat8L is important in psychiatric disease, addiction, and regulation of brain metabolism, and will continue to be the subject of extensive study in the future.

F. Guo et al., Ablating N-acetylaspartate prevents leukodystrophy in a Canavan disease model. Ann. Neurol. 77, 884–888 (2015). [Abstract]

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