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Please use this identifier to cite or link to this item: http://hdl.handle.net/10400.18/212

Título: Slc25a12 disruption alters myelination and neurofilaments: a model for a hypomyelination syndrome and childhood neurodevelopmental disorders
Autor: Sakurai, Takeshi
Ramoz, Nicolas
Barreto, Marta
Gazdoiu, Mihaela
Takahashi, Nagahide
Gertner, Michael
Dorr, Nathan
Gama Sosa, Miguel A.
De Gasperi, Rita
Perez, Gissel
Schmeidler, James
Mitropoulou, Vivian
Le, H. Carl
Lupu, Mihaela
Hof, Patrick R.
Elder, Gregory A.
Buxbaum, Joseph D.
Palavras-chave: Malate/aspartate shuttle
Mitochondria
N-acetylaspartate(NAA),
Neuron-oligodendrocyte interactions
Pyruvate
Determinantes da Saúde e da Doença
Issue Date: 1-May-2010
Editora: Elsevier
Citação: Biol Psychiatry. 2010 May 1;67(9):887-94. Epub 2009 Dec 16
Resumo: 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.
Arbitragem científica: yes
URI: http://hdl.handle.net/10400.18/212
ISSN: 0006-3223
Versão do Editor: http://www.sciencedirect.com/science/article/pii/S0006322309012062
Appears in Collections:DEP - Artigos em revistas internacionais

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