Misincorporation of the proline analog azetidine-2-carboxylic acid in the pathogenesis of multiple sclerosis: a hypothesis.
The misconstruction of proteins as a result of the displacement of one of more proline residues by their congener, azetidine-2-carboxylic acid (Aze), can result in various disorders. A number of lines of evidence suggest that multiple sclerosis may be among these. This concept adheres to the current view that multiple sclerosis lesions originate in the myelin sheath and that the underlying molecular abnormality involves the myelin basic protein. The Aze hypothesis posits that myelin basic protein and possibly other closely related molecules are misassembled in sites of lesion formation because of the substitution of Aze for one or more prolines within consensual epitopes. These include a highly conserved myelin basic protein hexapeptide sequence, PRTPPP, and an alpha helix bounded by prolyls. Recent studies have focused on the immunopathogenetic effects of posttranslational modification of this region. This hypothesis proposes that the domain is structurally, functionally, and antigenically altered by the intrusion of Aze in place of proline and that such misassembly may involve other proteins and adversely affect interactions with neighboring molecules. This report reviews evidence supporting the hypothesis that ingestion of Aze in the diet, in conjunction with genetic susceptibility, may predispose or contribute to the pathogenesis of multiple sclerosis.
Rubenstein
Edward
E
Department of Medicine, Stanford University School of Medicine, Stanford, California, USA. exr@stanford.edu
D000818:Animals; D001383:Azetidinecarboxylic Acid / Q000009:adverse effects*; D049672:History, 19th Century; D049673:History, 20th Century; D006801:Humans; D008954:Models, Biological; D009103:Multiple Sclerosis / Q000453:epidemiology / Q000209:etiology* / Q000266:history / Q000473:pathology*; D009186:Myelin Sheath / Q000473:pathology / Q000648:ultrastructure; D011392:Proline / Q000031:analogs & derivatives
D001383:Azetidinecarboxylic Acid; D011392:Proline