Excitotoxicity in ALS

Excitotoxicity has been suggested as one mechanism by which motor neurons are damaged in ALS. About 60-70% of sporadic ALS patients have a 30-95% reduction in the astroglial glutamate transporter EAAT2 (excitatory amino acid transporter 2), also termed GLT-1 in motor cortex and spinal cord. Loss of the major transporter could lead to an increase in extracellular concentrations of glutamate, as seen in some patients with ALS, and excitotoxic degeneration of motor neurons. Significantly, in a subset of patients with sporadic ALS (65%), multiple abnormalities of EAAT2 mRNA, including intron retention and exon skipping, have initially been identified in tissues from the affected areas. The aberrant mRNAs were highly abundant, found only in neuropathologically affected areas of ALS patients and not in other brain regions, and detectable in the CSF of living ALS patients early in the disease. In vitro expression studies suggest that proteins translated from these aberrant mRNA can undergo rapid degradation and/or produce dominantnegative effects on normal EAAT2, resulting in loss of protein and activity. These findings suggest that a reduction of EAAT2 in ALS could be due to the presence of aberrant EAAT2 mRNA, presumably resulting from RNA processing errors. This aberrant RNA processing reduces the levels of this type of glutamate transport, and accumulation of glutamate could predispose to excitotoxic damage of motor neurons. Consistent with this idea is the finding that experimental reductions in EAAT2 by antisense olgonucleotide injection in vivo produce progressive limb weakness and motor neuron degeneration. However, recent observations have shown that these aberrant EAATS mRNAs were also found in control cases. The significance of these aberrant mRNAs in ALS pathogenesis remains a focus of future research.

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