Reduced N-acetylaspartate levels in mice lacking aralar, a brain- and muscle-type mitochondrial aspartate-glutamate carrier.

This work is important because it has established that the malate-aspartate-nicotinamide adenine dinucleotide (NADH) shuttle in neuronal mitochondria is relevant for the cellular metabolism of myelinating glia.

In neurons, the aspartate-glutamate carrier aralar (also termed Slc25A12 or AGC1) transports aspartate from mitochondria into the cytosol, where it is converted into the metabolite N-acetylaspartate (NAA) that is transferred to oligodendrocytes. NAA-derived acetyl groups are believed to be rate-limiting for the generation of myelin lipids such as galactosyl cerebroside (GalC). The authors show that aralar-deficient mice have diminished levels of aspartate, NAA, and GalC in their brains, a likely cause of impaired myelination, growth retardation, tremor, impaired motor capabilities and premature death. A direct link from galactolipid-deficiency to hypomyelination is indicated by the fact that mice lacking the enzyme UDP-galactose:ceramide galactosyltransferase (CGT), required for synthesizing galactolipids, harbor a significantly decreased number of myelinated axon segments, {1}, though it is important to note that the neurological phenotype of CGT-deficient mice is much milder than that that of aralar-deficient mice. This work also has established aralar as a candidate gene for myelin disease in humans, and indeed one patient with global cerebral hypomyelination has been identified as carrying a homozygous mutation (Q390R) affecting aralar {2}.

References: {1} Marcus et al. Glia 2000, 30:319-28 [PMID:10797612]. {2} Wibom et al. N Engl J Med 2009, 361:489-95 [PMID:19641205].