These insults can arise from ischemic, hypoxic, and traumatic events as well as poisoning by environmental agents such as carbon monoxide. Receptors for glutamate, the principal excitatory transmitter in the mammalian nervous system, are pivotal in mediating these toxic insults. One aspect of our recent work centers on a neurotoxic insult mediated by autoantibodies to a particular form of glutamate receptor, GluR3. We have discovered that a neurodegenerative disease of humans is caused, at least in part, by autoantibodies targeting this receptor. We have also discovered the mechanism by which these autoantibodies trigger the execution of neurons, namely by activation of the complement cascade.
Similar mechanisms are likely to be operative in a diversity of neurodegenerative diseases.
Current projects are aimed at identifying the environmental factors triggering this immune attack on the nervous system, mapping the epitopes targeted by the antibodies, and developing therapies based upon this information. A diversity of models are used in our research including material from humans with diverse diseases, in vivo models in mice, and multiple in vitro models, including neurons in primary culture, and organotypic explant cultures. Glutamate receptor GluR3 antibodies and death of cortical cells. Requirement for superoxide in excitotoxic cell death. Autoantibodies to glutamate receptor GluR3 in Rasmussen's encephalitis.