Rapid and efficient uptake of
glutamate via the high-affinity
glutamate transporter EAAT2 is important for limiting
glutamate-mediated excitotoxicity involved in neuronal death. Furthermore, there is evidence of altered
glutamate uptake and catabolism in
motor neuron diseases. Such a defect has been reported in
amyotrophic lateral sclerosis, the major
motor neuron disease, and was associated with impairment in EAAT2 processing. We recently reported the presence of enterovirus genome specifically in the anterior horn of
amyotrophic lateral sclerosis cases, suggesting the involvement of a chronic/persistent
enterovirus infection in
amyotrophic lateral sclerosis. To investigate a putative link between
enterovirus infection and the
glutamate-mediated excitotoxicity observed in
amyotrophic lateral sclerosis, we developed an in vitro model consisting of a human glial cell line infected with ECHOvirus 6, one of the enteroviruses with sequences closely related to those detected in patients with
amyotrophic lateral sclerosis. In these glial cells, an ECHOvirus 6
chronic infection was established, resulting in altered extracellular
glutamate uptake. This correlated with an aberrant splicing of the EAAT2 pre-messenger
ribonucleic acid and a significant loss of EAAT2
protein expression, similar to that observed in patients with
amyotrophic lateral sclerosis. These results provide convincing evidence that an enterovirus chronic/
persistent infection may alter glial
glutamate uptake and catabolism. As enteroviruses are extremely common human pathogens, they may act as a trigger in the development of certain
motor neuron diseases, such as
amyotrophic lateral sclerosis.