Journal
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
Volume 67, Issue 11, Pages 1035-1040Publisher
OXFORD UNIV PRESS INC
DOI: 10.1097/NEN.0b013e31818add4a
Keywords
Azetidine-2-carboxylic acid (Aze); Ion channel; Multiple sclerosis; Teratogenesis; Translation
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Funding
- Technology Innovation Fund, Beckman Center, Stanford University Medical Center, Stanford, CA
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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 a 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.
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