title: 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.
authors.affiliation: Department of Biological Sciences and School of Biomedical Sciences, Kent State University, Kent, OH, 44242, USA.
authors.forename: N K
authors.initials: NK
authors.lastname: Singhal
authors.affiliation: Department of Chemistry and Biology, University of Akron, Akron, OH, 44325, USA.
authors.forename: H
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Biological Sciences and School of Biomedical Sciences, Kent State University, Kent, OH, 44242, USA.
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Biological Sciences and School of Biomedical Sciences, Kent State University, Kent, OH, 44242, USA.
authors.forename: R
authors.initials: R
authors.lastname: Clements
authors.affiliation: Department of Biological Sciences and School of Biomedical Sciences, Kent State University, Kent, OH, 44242, USA.
authors.forename: J
authors.initials: J
authors.lastname: Gadd
authors.affiliation: Department of Biological Sciences and School of Biomedical Sciences, Kent State University, Kent, OH, 44242, USA.
authors.forename: A
authors.initials: A
authors.lastname: Daniels
authors.affiliation: Department of Biological Sciences and School of Biomedical Sciences, Kent State University, Kent, OH, 44242, USA.
authors.forename: E E
authors.initials: EE
authors.lastname: Kooijman
authors.affiliation: Department of Cell Biology and Human Anatomy, UC Davis School of Medicine, Sacramento, CA, 95817, USA.
authors.forename: P
authors.initials: P
authors.lastname: Bannerman
authors.affiliation: Department of Neurology, UC Davis School of Medicine, Sacramento, CA, 95817, USA.
authors.forename: T
authors.initials: T
authors.lastname: Burns
authors.affiliation: Department of Neurology, UC Davis School of Medicine, Sacramento, CA, 95817, USA.
authors.forename: F
authors.initials: F
authors.lastname: Guo
authors.affiliation: Department of Neurology, UC Davis School of Medicine, Sacramento, CA, 95817, USA.
authors.forename: D
authors.initials: D
authors.lastname: Pleasure
authors.affiliation: Department of Biological Sciences and School of Biomedical Sciences, Kent State University, Kent, OH, 44242, USA.
authors.forename: E
authors.initials: E
authors.lastname: Freeman
authors.affiliation: Department of Chemistry and Biology, University of Akron, Akron, OH, 44325, USA.
authors.forename: L
authors.initials: L
authors.lastname: Shriver
authors.affiliation: Department of Biological Sciences and School of Biomedical Sciences, Kent State University, Kent, OH, 44242, USA. jmcdonou@kent.edu.
authors.forename: J
authors.initials: J
authors.lastname: McDonough
mesh_terms: D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D002490:Central Nervous System / Q000473:pathology*; D002853:Chromatography, Liquid; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007656:Ketoglutaric Acids / Q000378:metabolism; D008297:Male; D008745:Methylation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000473:pathology*; D009186:Myelin Sheath / Q000473:pathology*; D009474:Neurons / Q000187:drug effects*; D009836:Oligodendroglia; D011180:Postmortem Changes; D053719:Tandem Mass Spectrometry
chemical_list: D006657:Histones; D007656:Ketoglutaric Acids; D001224:Aspartic Acid; C000179:N-acetylaspartate; D000123:Acetyltransferases; C521704:Shati protein, mouse
keywords: Histone methylation; Mass spectrometry; Multiple sclerosis; Myelin lipids; N-acetylaspartate; Oligodendrocytes