Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis.
The pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) is unknown, but defects in synaptosomal high-affinity glutamate transport have been observed. In experimental models, chronic loss of glutamate transport can produce a loss of motor neurons and, therefore, could contribute to the disease. With the recent cloning of three glutamate transporters, i.e., EAAC1, GLT-1, and GLAST, it has become possible to determine if the loss of glutamate transport in ALS is subtype specific. We developed C-terminal, antioligopeptide antibodies that were specific for each glutamate transporter. EAAC1 is selective for neurons, while GLT-1 and GLAST are selective for astroglia. Tissue from various brain regions of ALS patients and controls were examined by immunoblot or 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 compared with control) and in spinal cord. In approximately a quarter of the ALS motor cortex specimens, the loss of GLT-1 protein (90% decrease from control) was dramatic. By contrast, there was only a modest loss (20% decrease from control) of immunoreactive protein EAAC1 in ALS motor cortex, and there was no appreciable change in GLAST. The minor loss of EAAC1 could be secondary to loss of cortical motor neurons. As a comparison, glial fibrillary acidic protein, which is selectively localized to astroglia, was not changed in ALS motor cortex. Because there 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.
Rothstein
J D
JD
Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
Van Kammen
M
M
Levey
A I
AI
Martin
L J
LJ
Kuncl
R W
RW
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000368:Aged; D000595:Amino Acid Sequence; D027322:Amino Acid Transport System X-AG; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000906:Antibodies / Q000378:metabolism; D000918:Antibody Specificity; D001253:Astrocytes / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009044:Motor Cortex / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D016708:Synaptophysin / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG; D000906:Antibodies; D002352:Carrier Proteins; D005904:Glial Fibrillary Acidic Protein; D006023:Glycoproteins; D010446:Peptide Fragments; D016708:Synaptophysin