A neuronal gene mutation that kills glia

A great number of demyelination disorders have been identified such as multiple sclerosis, the most common neurological disorder affecting 0.2% of young adults. Myelinating cells, specifically oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS), produce a vast amount of myelin as an extension of their plasma membrane (1, 2). Myelin, also known as white matter, is a unique, lipid-rich multilamellar sheath that wraps around axons in the CNS and PNS. It is essential for the fast conduction of the action potential along axons as well as the maintenance of axonal integrity (3). Hypomyelination leads to severe defects in the development and function of the nervous system (4–10). The objective of this clinical study is to identify the underlying cause of a novel syndrome, characterized by arrested psychomotor development, hypotonia and seizures, in the 3-year-old female patient. Magnetic resonance imaging (MRI) of this patient showed a striking global cerebral hypomyelination with relatively spared gray matter. A missense mutation (Q590R) in the SLC25A12 gene, encoding the mitochondrial aspartate–glutamate carrier isoform 1 (AGC1), was identified in this patient. AGC1, specific to neurons and muscle, catalyzes an exchange between mitochondrial aspartate and cytosolic glutamate (11). As a component of the malate–aspartate shuttle, AGC1 also enables mitochondrial oxidation of cytosolic nicotinamide adenine dinucleotide hydrogenase (NADH), thought to be important in providing energy for neurons in the CNS (12) (Fig. 1). Considering its crucial role in the survival of neurons, it is surprising that the gray matter, basal ganglia and brainstem of the patient were relatively spared. Therefore, this study does not support the traditional belief that AGC1 deficiency results in compromised neuronal energy production as a major pathogenetic mechanism. Instead, it reveals a novel role of neuronal AGC1 in the survival of glia cells, specifically oligodrendrocytes that form myelin in the CNS. In neurons, AGC1 transports aspartate from mitochondria to the cytosol in order to synthesize N -acetyl aspartate (13)]. N -acetyl aspartate undergoes transaxonal transfer from neurons to oligodrendrocytes and supplies acetyl groups for the synthesis of myelin lipids (14, 15) (Fig. 1). Survival of myelinating cells requires synthesis of an enormous amount of myelin membrane proteins, cholesterol and membrane lipids (1). Thus, it is not surprising that myelinating cells are highly sensitive to mutations of a gene product that disrupts these pathways. In vitro, recombinant AGC1 with the Q590R mutation was unable to transport aspartate or glutamate. Indeed, the patient with this mutation also had reduced N -acetyl aspartate. These findings are also concordant with the phenotype of AGC1knockout mice which exhibit motor-coordination deficits along with impaired myelination in the CNS. Levels of aspartate and N -acetyl aspartate in the CNS of these mice are also significantly lower. Taken together, these results support the hypothesis that the major pathogenetic mechanism of the syndrome is the impaired neuronal aspartate transport, which prevents myelin formation by failing to provide N -acetyl aspartate to oligodendrocytes. However, neurons from both the patient and the AGC1-knockout mice are relatively spared, suggesting that the malate–aspartate shuttle is not essential for the survival of neurons. The glycerol3-phosphate cycle, known to be active in the brain, is an alternative pathway of transfer for reducing equivalents into the mitochondria (16). Therefore, it may compensate for a compromised malate–aspartate shuttle in neurons in vivo. Another intriguing question derived from this study is why myelination formation is specifically disrupted in the cerebral hemisphere but remains normal in the cerebellum, brainstem and thalamus of the patient, despite the presence of the AGC1 mutation in these regions. Further, studies