A putative mechanism of demyelination in multiple sclerosis by a proteolytic enzyme, calpain.
In autoimmune demyelinating diseases such as multiple sclerosis (MS), the degradation of myelin proteins results in destabilization of the myelin sheath. Thus, proteases 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 controls, although levels of the specific endogenous inhibitor, calpastatin, were not altered significantly. At the transcriptional level, no significant changes in calpain or calpastatin expression were detected by reverse transcription-PCR. Using double immunofluorescent labeling, increased calpain expression was observed in reactive astrocytes, activated T cells, and activated mononuclear phagocytes in and adjacent to demyelinating 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 demyelinating diseases such as MS.
Shields
D C
DC
Department of Neurology, Medical University of South Carolina, 171 Ashley Avenue Charleston, SC 29425, USA.
Schaecher
K E
KE
Saido
T C
TC
Banik
N L
NL
D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000502:physiology; D002154:Calpain / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D003711:Demyelinating Diseases / Q000209:etiology; D005455:Fluorescent Antibody Technique; D006801:Humans; D009103:Multiple Sclerosis / Q000201:enzymology* / Q000209:etiology; D014176:Protein Biosynthesis; D014158:Transcription, Genetic
D002135:Calcium-Binding Proteins; C033668:calpastatin; D002154:Calpain; D002118:Calcium