A putative mechanism of demyelination in multiple sclerosis by a proteolytic enzyme, calpain

摘要

In autoimmune demyelinating diseases such as multiple sclerosis (MS), the degradation of myelin proteins results in destabilization of the myelin sheath. Thus, proleases have been implicated in myelin protein degradation, and recent studies have demonstrated increased expression and activity of a calcium-activated neutral proteinase (calpain) in experimental allergic encephalomyelitis, the corresponding animal model of MS. In the present study, calpain activity and expression (at translational and transcriptional levels) were evaluated in white matter from human patients with MS and Parkinson's and Alzheimer's diseases and compared with that of white matter from normal controls. Western blot analysis revealed that levels of the active form of calpain and calpain- specific degradation products (fodrin) were increased by 90.1 and 52.7, respectively, in MS plaques compared with normal white matter. Calpain translational expression was up-regulated by 462.5 in MS plaques compared with con- trols, although levels of the specific endogenous inhibitor, calpastatin, were not altered significantly. At the transcrip- tional level, no significant changes in calpain or calpastatin expression were detected by reverse transcription-PCR. Using double immunofluorescent labeling, increased calpain expres- sion was observed in reactive astrocytes, activated T cells, and activated mononuclear phagocytes in and adjacent to demy- elinating lesions. Calpain activity and translational expres- sion were not increased significantly in white matter from patients with Parkinson's or Alzheimer's di