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

Abstract

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.

SuppressingN-Acetyl-l-Aspartate Synthesis Prevents Loss of Neurons in a Murine Model of Canavan Leukodystrophy

“…There is as yet no proof that the modest decreases in [NAA B ] seen in neuroinflammatory/ neurodegenerative brain disorders as a consequence of brain mitochondrial dysfunction are themselves deleterious, although they may cause changes in CNS myelin lipid composition (Ciccarelli et al, 2010;Li et al, 2013;Singhal et al, 2016). However, obliteration of NAA synthesis by inactivation of both Nat8l alleles, although not causing dysmyelination or obvious motor deficits in Nat8l Ϫ/ Ϫ mice , has been associated with subtle behavioral abnormalities (Furukawa-Hibi et al, 2012;, and the one known human with documented homozygous NAT8L deletion was developmentally delayed, ataxic, and microcephalic (Martin et al, 2001;Wiame et al, 2009).…”

Emerging Role for Methylation in Multiple Sclerosis: Beyond DNA

“…However, ablation of H3K9 methyltransferases ( Ehmt2 and Suv39h1 ), but not H3K27 methyltransferases ( Ezh1/2 ), impaired murine OPC differentiation in vitro [71], suggesting that H3K9me3 might be essential for proper OPC function and myelination. Furthermore, reports of reduced H3K4me3 in MS NAGM neurons implicate lysine methylation in neuronal integrity, as evidenced by the correlation of reduced H3K4me3 with reduced betaine and mitochondrial respiration in MS patient brain tissue[22,72]. Therefore, non-lesional MS tissue may be at heightened risk of axonal damage [22] due to the inflammatory oxidative conditions typical of MS lesions.…”

NAT8LmRNA oxidation is linked to neurodegeneration in multiple sclerosis

“…Parkinson's disease, investigating the impact of oxidation on NAT8L mRNA is an obvious choice (25,30,32,41,42). Although, the reduction of NAA in the MS CNS is well established, implying a crucial role of NAA deficiency in MS progression, the reason behind the reduction is not known.…”

“…There are reports on the reduction of NAA level in the MS brain (32,35,46). In fact, the reduction of NAA in the brain has been used as a marker for detecting mitochondrial dysfunction in several neurological disorders including MS (32,35). of postmortem MS brain.…”

“…Nat8l knockout mice (Nat8l -/-) showed decreased NAA content in the brain, less compact myelin structure, reduced social interaction, and shortened immobility time in the forced swimming test (34). As demonstrated by magnetic resonance spectroscopy (MRS) studies on patients (33) and HPLC analysis of NAA in the postmortem MS brain extracts (32,35), the reduction of NAA is one of the pathological hallmarks in the CNS of MS patients.…”