Abstract
Background
Paraneoplastic syndromes are “remote” complications of cancer characterized clinically by neurological disease. The sera and cerebrospinal fluid (CSF) from patients with paraneoplastic neurological syndromes (PNS) frequently contain autoantibodies to ill-defined neuronal antigens. We report here that neuronal glutamate receptors are targets for autoantibodies found in the serum from some patients with well-characterized PNS.
Materials and Methods
We have analyzed the serum from seven patients with well-characterized PNS for the presence of autoreactive antibodies to non-NMDA glutamate receptor subunits. Autoantibodies were assessed using Western blot, immunohistochemistry, and immunocytochemistry. Whole-cell electrophysiological recordings were used to examine the effect of antibodies on glutamate receptors expressed by cortical neurons in culture.
Results
Six of seven patients’ serum contained autoantibodies to the non-NMDA glutamate receptor (GluR) subunits GluR1, GluR4, and/or GluR5/6. No patient had autoantibodies to GluR2, and only one patient exhibited weak immunoreactivity to GluR3. Electrophysiological analysis demonstrated that the serum from four of the six GluR-antibody-positive patients enhanced glutamate-elicited currents on cultured cortical neurons but had no effect on receptor function alone. Enhancement of glutamate-elicited currents was also produced by affinity-purified antibody to GluR5.
Conclusions
The occurrence of autoantibodies to specific neuronal neurotransmitter subunits in the sera of patients with PNS and the ability of these autoantibodies to modulate glutaminergic receptor function suggest that some paraneoplastic neurological injury could result from glutamate-mediated excitotoxicity.
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Acknowledgments
This research was supported by National Institutes of Health Grants NS30990 and AG04418 to SWR and N531519 to RET, the American Federation for Aging Research and American Cancer Society Institutional Research grant to LCG and a U.S. Department of Veterans Affairs Merit Review grant to JG. The authors thank Jessica Tingey for excellent technical assistance. The authors would also like to express their gratitude to Dr. Richard Smith, Denver, CO, and Dr. H. Robert Brashear, University of Virginia, for providing sera from Patients 1 and 3.
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Gahring, L.C., Twyman, R.E., Greenlee, J.E. et al. Autoantibodies to Neuronal Glutamate Receptors in Patients with Paraneoplastic Neurodegenerative Syndrome Enhance Receptor Activation. Mol Med 1, 245–253 (1995). https://doi.org/10.1007/BF03401549
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DOI: https://doi.org/10.1007/BF03401549