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Slc25a12 disruption alters myelination and neurofilaments: a model for a hypomyelination syndrome and childhood neurodevelopmental disorders

2010-05-01Journal article Open access
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dc.contributor.authorSakurai, Takeshi
dc.contributor.authorRamoz, Nicolas
dc.contributor.authorBarreto, Marta
dc.contributor.authorGazdoiu, Mihaela
dc.contributor.authorTakahashi, Nagahide
dc.contributor.authorGertner, Michael
dc.contributor.authorDorr, Nathan
dc.contributor.authorGama Sosa, Miguel A.
dc.contributor.authorDe Gasperi, Rita
dc.contributor.authorPerez, Gissel
dc.contributor.authorSchmeidler, James
dc.contributor.authorMitropoulou, Vivian
dc.contributor.authorLe, H. Carl
dc.contributor.authorLupu, Mihaela
dc.contributor.authorHof, Patrick R.
dc.contributor.authorElder, Gregory A.
dc.contributor.authorBuxbaum, Joseph D.
dc.date.accessioned2011-09-19T16:25:47Z
dc.date.available2011-09-19T16:25:47Z
dc.date.issued2010-05-01
dc.description.abstractBACKGROUND: 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.por
dc.identifier.citationBiol Psychiatry. 2010 May 1;67(9):887-94. Epub 2009 Dec 16por
dc.identifier.issn0006-3223
dc.identifier.otherdoi:10.1016/j.biopsych.2009.08.042
dc.identifier.urihttp://hdl.handle.net/10400.18/212
dc.language.isoengpor
dc.peerreviewedyespor
dc.publisherElsevierpor
dc.relation.publisherversionhttp://www.sciencedirect.com/science/article/pii/S0006322309012062por
dc.subjectMalate/aspartate shuttlepor
dc.subjectMitochondriapor
dc.subjectN-acetylaspartate(NAA),por
dc.subjectNeuron-oligodendrocyte interactionspor
dc.subjectPyruvatepor
dc.subjectDeterminantes da Saúde e da Doençapor
dc.titleSlc25a12 disruption alters myelination and neurofilaments: a model for a hypomyelination syndrome and childhood neurodevelopmental disorderspor
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage894por
oaire.citation.startPage887por
oaire.citation.titleBiological Psychiatrypor
rcaap.rightsrestrictedAccesspor
rcaap.typearticlepor

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