Structural insight into the role of myelin basic protein in multiple sclerosis.

I n the article by Musse et al. in this issue of PNAS (1), the authors present unique and compelling physico-chemical data that demonstrate the structural instability of myelin in multiple sclerosis (MS). Such alteration in myelin stability, reported as secondary to changes in myelin basic protein (MBP) structure, may be causative in nature and or contribute to the early course of demyelination in MS. A combination of physico-chemical and theoretical approaches enabled the authors to arrive at their conclusions and demonstrated that myelin structural information can shed light on mechanistic dysfunction in MS. The primary findings are that an altered charge isomer of MBP (rmC8) that is associated with disease severity in MS (2) has less membrane depth penetration and shorter -helix structure, making the immunodominant epitope of this protein more exposed to the cytosolic space and readily digested by proteases. This change in MBP conformation would free the epitope for T cell recognition and suggests a mechanism of action potentially initiated by alterations in myelin structure. This hypothesis is supported by a recent study describing antibody enzymes (abzymes) that catalyze MBP in a sitespecific degradation (3). The C8 MBP isoform is also more abundant in immature myelin, and results of this study support the hypothesis that myelin structure in MS is developmentally immature (4), contributing to altered myelin stability and possibly the initiation of the disease.