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

Autor: A. Daniels, Leah P. Shriver, Robert Clements, E. E. Kooijman, Peter Bannerman, Shuo Li, Jennifer McDonough, He Huang, Naveen Kumar Singhal, Fuzheng Guo, Travis Burns, David E Pleasure, Ernest J. Freeman, J. Gadd
Rok vydání: 2016
Předmět:
Central Nervous System
Male
0301 basic medicine
Neurodegenerative
Inbred C57BL
Medical and Health Sciences
Transgenic
Histone methylation
Histones
Mice
Myelin
Myelin lipids
N-acetylaspartate
0302 clinical medicine
Tandem Mass Spectrometry
Cells
Cultured
Myelin Sheath
Neurons
Chromatography
Liquid
Cultured
Oligodendrocytes
Chemistry
General Neuroscience
Cell biology
Oligodendroglia
medicine.anatomical_structure
Neurological
Ketoglutaric Acids
Female
Sphingomyelin
Multiple Sclerosis
Cells
1.1 Normal biological development and functioning
Mice
Transgenic
Autoimmune Disease
Methylation
Article
White matter
03 medical and health sciences
Histone H3
Underpinning research
Acetyltransferases
mental disorders
Genetics
medicine
Animals
Humans
Histone demethylase activity
Aspartic Acid
Neurology & Neurosurgery
Mass spectrometry
Psychology and Cognitive Sciences
Neurosciences
Oligodendrocyte
Brain Disorders
nervous system diseases
Aspartoacylase
Mice
Inbred C57BL
030104 developmental biology
Gene Expression Regulation
nervous system
Postmortem Changes
Neuroscience
030217 neurology & neurosurgery
Chromatography
Liquid
Zdroj: Experimental brain research, vol 235, iss 1
ISSN: 1432-1106
0014-4819
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: