SELECTIVE LOSS OF GLIAL GLUTAMATE TRANSPORTER GLT-1 IN AMYOTROPHIC-LATERAL-SCLEROSIS

The pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) is un known, but defects in synaptosomal high-affinity glutamate transport h ave been observed. In experimental models, chronic loss of glutamate t ransport can produce a loss of motor neurons and, therefore, could con tribute to the disease. With the recent cloning of three glutamate tra nsporters, i.e., EAAC1, GLT-1, and GLAST, it has become possible to de termine if the loss of glutamate transport in ALS is subtype specific. We developed C-terminal, antioligopeptide antibodies that were specif ic for each glutamate transporter. EAAC1 is selective for neurons, whi le GLT-1 and GLAST are selective for astroglia. Tissue from various br ain regions of ALS patients and controls were examined by immunoblot o r immunocytochemical methods for each transporter subtype. All tissue was matched for age and postmortem delay. GLT-1 immunoreactive protein was severely decreased in ALS, both in motor cortex (71% decrease com pared with control) and in spinal cord. In approximately a quarter of the ALS motor cortex specimens, the loss of GLT-1 protein (90% decreas e from control) was dramatic. By contrast, there was only a modest los s (20% decrease from control) of immunoreactive protein EAAC1 in ALS m otor cortex, and there was no appreciable change in GLAST. The minor l oss of EAAC1 could be secondary to loss of cortical motor neurons. As a comparison, glial fibrillary acidic protein, which is selectively lo calized to astroglia, was not changed in ALS motor cortex. Because the re is no loss of astroglia in ALS, the dramatic abnormalities in GLT-1 could reflect a primary defect in GLT-1 protein, a secondary loss due to down regulation, or other toxic processes.