Is autoimmunity in multiple sclerosis secondary to neurodegeneration?

Abstract

Abstract Multiple sclerosis (MS) is characterized by neurological symptoms that are separated in time and space, which correlate with demyelination and white matter lesions. The conventional pathophysiological model is that an autoimmune reaction against the myelinated nerve sheath results in demyelination, accompanied by axon damage and the death of oligodendrocytes that produce myelin. There is no cure for MS, but current treatments are primarily aimed at suppressing the autoimmune reaction, with the goal of reducing demyelination. These treatments have limited efficacy and developing better treatments for MS remains an important goal. Here we argue that the autoimmune reaction may be secondary to neurodegeneration or neurotoxicity, and that protecting neurons from glutamate-mediated toxicity may be a better therapeutic strategy than targeting the immune system. We have recently demonstrated that a protein-protein interaction between the GluR2 subunit of the AMPA (α-Amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid) glutamate receptor and GAPDH (Glyceraldehyde 3-phosphate dehydrogenase) is elevated in human MS plaques and in an animal model of MS. Disrupting this interaction in a rodent model restores neurological function, preserves myelin, and protects neurons, oligodendrocytes and axons. The peptide we created to block the GluR2-GAPDH interaction also reduces immune system activation, suggesting that autoimmunity is not necessarily the primary etiology in MS. The GluR2-GAPDH interaction may promote cell death via increased calcium influx through non-GluR2-containing AMPA receptors, or through the p53 and Siah1 cell death pathways.

Keywords

multiple sclerosis (MS), autoimmunity,GluR2, GAPDH