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

In autoimmune demyelinating diseases such as multiple sclerosis (MS), the d egradation of myelin proteins results in destabilization of the myelin shea th. Thus, proteases have been implicated in myelin protein degradation, and recent studies have demonstrated increased expression and activity of a ca lcium-activated neutral proteinase (calpain) in experimental allergic encep halomyelitis, the corresponding animal model of MS. In the present study, c alpain 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 norm al controls. Western blot analysis revealed that levels of the active form of calpain and calpain-specific degradation products (fodrin) were increase d by 90.1% and 52.7%, respectively, in MS plaques compared with normal whit e matter. Calpain translational expression was up-regulated by 462.5% in MS plaques compared with controls, although levels of the specific endogenous inhibitor, calpastatin, were not altered significantly. At the transcripti onal level, no significant changes in calpain or calpastatin expression wer e detected by reverse transcription-PCR. Using double immunofluorescent lab eling, increased calpain expression was observed in reactive astrocytes, ac tivated T cells, and activated mononuclear phagocytes in and adjacent to de myelinating lesions. Calpain activity and translational expression were not increased significantly in white matter from patients with Parkinson's or Alzheimer's diseases compared with that of normal controls. Because calpain degrades all major myelin proteins, the increased activity and expression of this proteinase may play a critical role in myelinolysis in autoimmune d emyelinating diseases such as MS.