Ablating <scp>N</scp>‐acetylaspartate prevents leukodystrophy in a <scp>C</scp>anavan disease model

Guo, Fuzheng; Bannerman, Peter; Ko, Emily Mills; Miers, Laird; Xu, Jie; Burns, Travis; Li, Shuo; Freeman, Ernest J.; McDonough, Jennifer; Pleasure, David E

doi:10.1002/ana.24392

Cited by 50 publications

(62 citation statements)

References 22 publications

(27 reference statements)

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“…To test directly whether depletion of NAA causes changes in myelin lipids, we analyzed brains from 1-year-old NAT8L −/− mice by mass spectrometry and HPTLC. The enzyme NAT8L synthesizes NAA, and it has been shown that NAA is not synthesized in NAT8L −/− mice (Guo et al 2015). Analyzing myelin lipids from the brains of these mice, we found significant decreases in sphingomyelin (SM), phosphatidylcholine (PC), phosphatidylserine (PS), and phosphatidic acid (PA) by LC−MS/MS (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, the enzyme which synthesizes NAA in neurons, NAT8L, has been knocked out in mice, and surprisingly early analyses of these mice by transmission electron microscopy (TEM) suggest that they appear to myelinate normally even though NAA has been shown to be absent (Guo et al 2015). However, at 2 months g-ratios were found to be decreased in NAT8L −/− mice, indicating thicker myelin in the corpus callosum (Guo et al 2015).…”

Section: Introductionmentioning

confidence: 99%

“…However, at 2 months g-ratios were found to be decreased in NAT8L −/− mice, indicating thicker myelin in the corpus callosum (Guo et al 2015). Changes in myelin lipid composition have not been analyzed in these mice.…”

Section: Introductionmentioning

confidence: 99%

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The neuronal metabolite NAA regulates histone H3 methylation in oligodendrocytes and myelin lipid composition

Singhal

Huang

et al. 2016

Exp Brain Res

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The neuronal mitochondrial metabolite N-acetylaspartate (NAA) is decreased in the multiple sclerosis (MS) brain. NAA is synthesized in neurons by the enzyme N-acetyltransferase-8-like (NAT8L) and broken down in oligodendrocytes by aspartoacylase (ASPA) into acetate and aspartate. We have hypothesized that NAA links the metabolism of axons with oligodendrocytes to support myelination. To test this hypothesis, we performed lipidomic analyses using liquid chromatography–tandem mass spectrometry (LC–MS/MS) and high-performance thin-layer chromatography (HPTLC) to identify changes in myelin lipid composition in postmortem MS brains and in NAT8L knockout (NAT8L−/−) mice which do not synthesize NAA. We found reduced levels of sphingomyelin in MS normal appearing white matter that mirrored decreased levels of NAA. We also discovered decreases in the amounts of sphingomyelin and sulfatide lipids in the brains of NAT8L−/− mice compared to controls. Metabolomic analysis of primary cultures of oligodendrocytes treated with NAA revealed increased levels of α-ketoglutarate, which has been reported to regulate histone demethylase activity. Consistent with this, NAA treatment resulted in alterations in the levels of histone H3 methylation, including H3K4me3, H3K9me2, and H3K9me3. The H3K4me3 histone mark regulates cellular energetics, metabolism, and growth, while H3K9me3 has been linked to alterations in transcriptional repression in developing oligodendrocytes. We also noted the NAA treatment was associated with increases in the expression of genes involved in sulfatide and sphingomyelin synthesis in cultured oligodendrocytes. This is the first report demonstrating that neuronal-derived NAA can signal to the oligodendrocyte nucleus. These data suggest that neuronal-derived NAA signals through epigenetic mechanisms in oligodendrocytes to support or maintain myelination.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The neuronal metabolite NAA regulates histone H3 methylation in oligodendrocytes and myelin lipid composition

Singhal

Huang

et al. 2016

Exp Brain Res

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“…We postulate a metabolic sink theory for CD in which reduction of NAA levels independent of the metabolizing glial cell type is therapeutic, since neuronal expression of ASPA has been shown to have limited therapeutic effect (32). This theory implies that either a compensating mechanism for oligodendroglial NAA exists as inferred from the work of others (41,42) or the function of NAA can be rerouted to astrocytes to provide essential metabolites to oligodendrocytes (43). Given the metabolic connections among glial cells, it would not be surprising if metabolic support is not only provided from glia to neurons but also among glial cells, potentially establishing the NAA metabolism in astrocytes to provide aspartate and acetate to oligodendrocytes (44).…”

Section: Discussionmentioning

confidence: 98%

Redirecting N-acetylaspartate metabolism in the central nervous system normalizes myelination and rescues Canavan disease

Gessler¹,

Li²,

Xu³

et al. 2017

JCI Insight

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“…Interestingly, while drafting this article, Guo et al (2015) have provided a very important study in support of the "osmotic-hydrostatic" theory (for which Lisupplementation appears as a therapeutic option). On the other hand, the supplementation of Ac through GTA has shown promise when in animal tests, but as of yet fails to achieve clinical improvements in human studies, perhaps due to late onset of the attempted treatment (Table 2).…”

Section: Resultsmentioning

confidence: 99%