Slc25a12 disruption alters myelination and neurofilaments: A model for a hypomyelination syndrome and childhood neurodevelopmental disorders Journal Article
| Authors: | Sakurai, T.; Ramoz, N.; Barreto, M.; Gazdoiu, M.; Takahashi, N.; Gertner, M.; Dorr, N.; Gama Sosa, M. A.; De Gasperi, R.; Perez, G.; Schmeidler, J.; Mitropoulou, V.; Le, H. C.; Lupu, M.; Hof, P. R.; Elder, G. A.; Buxbaum, J. D. |
| Article Title: | Slc25a12 disruption alters myelination and neurofilaments: A model for a hypomyelination syndrome and childhood neurodevelopmental disorders |
| Abstract: | Background: SLC25A12, a susceptibility gene for autism spectrum disorders that is mutated in a neurodevelopmental syndrome, encodes a mitochondrial aspartate-glutamate carrier (aspartate-glutamate carrier isoform 1 [AGC1]). AGC1 is an important component of the malate/aspartate shuttle, a crucial system supporting oxidative phosphorylation and adenosine triphosphate production. Methods: We characterized mice with a disruption of the Slc25a12 gene, followed by confirmatory in vitro studies. Results: Slc25a12-knockout mice, which showed no AGC1 by immunoblotting, were born normally but displayed delayed development and died around 3 weeks after birth. In postnatal day 13 to 14 knockout brains, the brains were smaller with no obvious alteration in gross structure. However, we found a reduction in myelin basic protein (MBP)-positive fibers, consistent with a previous report. Furthermore, the neocortex of knockout mice contained abnormal neurofilamentous accumulations in neurons, suggesting defective axonal transport and/or neurodegeneration. Slice cultures prepared from knockout mice also showed a myelination defect, and reduction of Slc25a12 in rat primary oligodendrocytes led to a cell-autonomous reduction in MBP expression. Myelin deficits in slice cultures from knockout mice could be reversed by administration of pyruvate, indicating that reduction in AGC1 activity leads to reduced production of aspartate/N-acetylaspartate and/or alterations in the dihydronicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide+ ratio, resulting in myelin defects. Conclusions: Our data implicate AGC1 activity in myelination and in neuronal structure and indicate that while loss of AGC1 leads to hypomyelination and neuronal changes, subtle alterations in AGC1 expression could affect brain development, contributing to increased autism susceptibility. © 2010 Society of Biological Psychiatry. |
| Keywords: | controlled study; unclassified drug; nonhuman; myelin basic protein; mouse; animals; mice; mice, knockout; animal tissue; cerebellum; purkinje cell; cells, cultured; animal experiment; neurons; gene expression regulation, developmental; brain; stem cells; green fluorescent proteins; neocortex; embryo, mammalian; animals, newborn; organ culture techniques; disease models, animal; encephalitis; mitochondrial protein; mitochondria; brain protein; myelination; receptors, cell surface; nerve degeneration; pyruvic acid; mitochondrial proteins; oligodendroglia; membrane transport proteins; malate/aspartate shuttle; n-acetylaspartate (naa); neuron-oligodendrocyte interactions; pyruvate; aspartate glutamate carrier isoform 1; protein slc25a12; neurofilament; aggrecans; calcium-binding protein, vitamin d-dependent; developmental disabilities; myelin basic proteins |
| Journal Title: | Biological Psychiatry |
| Volume: | 67 |
| Issue: | 9 |
| ISSN: | 0006-3223 |
| Publisher: | Elsevier Science, Inc. |
| Date Published: | 2010-05-01 |
| Start Page: | 887 |
| End Page: | 894 |
| Language: | English |
| DOI: | 10.1016/j.biopsych.2009.08.042 |
| PUBMED: | 20015484 |
| PROVIDER: | scopus |
| PMCID: | PMC4067545 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 3" - "Export Date: 20 April 2011" - "CODEN: BIPCB" - "Source: Scopus" |
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