Unbe‐leaf‐able! Aquaporin‐4's Connection to Neuromyelitis Optica

Abstract

Neuromyelitis optica (NMO) is an incurable disease with debilitating symptoms that occurs when autoantibodies attack and destroy the water channel protein Aquaporin-4 (AQP4), located in the endfeet of astrocytes in the optic nerve, spinal cord, and brain. Our research on AQP4's role in NMO focused on the AQP-M23 isoform. The autoantibody Immunoglobulin G (IgG) can bind to epitopes on AQP4; this interaction is linked to neuroautoimmune disorders, specifically NMO. We hypothesized that structural similarities between certain plant AQPs and human AQP4 could be a trigger for neurological disorders. Individuals may develop an antigenic reaction to AQP by consuming plants high in AQP; the dietary antibodies produced could mistake human AQP4 for a particular plant AQP and attack it by crossing a compromised blood-brain barrier, leading to a neuroautoimmune response. It is essential to understand the relationship between AQP4's structure and IgG to better understand the cause for NMO and other neuroautoimmune disorders so that we can find more effective forms of treatment and propose potential cures. Additionally, it is important to know if there is a link between the consumption of plants high in AQP and the development of neuroautimmune disorders; if so, at-risk individuals with a damaged blood-brain barrier can avoid consuming AQP-rich foods. To identify possible binding sites between AQP4 and IgG, we examined the properties of extracellular loops A, C, and E in AQP4, focusing on amino acid residues 207-232 located on loop E. This segment of AQP4 has portions of its sequence that are identical to the corresponding portions on spinach, corn, soybean, and tomato AQP. We hypothesized that there might be a possible epitope for IgG binding within these residues on loop E. We used our research to then identify other possible locations for epitopes on AQP4 by analyzing the hydrophobicity and size of potential binding residues. To do this, we used the human AQP4 Protein Data Bank file, 3GD8, and Jmol molecular modeling software to highlight possible epitope locations and examine the structural changes that will occur when IgG binds to AQP4. We also highlighted variations between human AQP4 and plant AQP, specifically spinach AQP, which is the most commonly reactive. The Mahtomedi MSOE Center for BioMolecular Modeling MAPS Team used 3-D modeling and printing technology to examine the structure-function relationships of AQP4 in autoantibody binding. The visual model was a valuable tool in developing our story.