Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0014070 (encephalomyelitis)
 13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism by which the myelin sheath is degraded in demyelinating diseases is unknown. The demonstration of increased activities of both acid (cathepsins B, D, A) and neutral proteinases in tissue from experimental allergic encephalomyelitis (EAE) in animals and multiple sclerosis (MS, plaques) and the disappearance of myelin proteins implicate a role for proteolytic enzyme in myelin breakdown. The degradation of myelin basic protein (MBP) by proteinase yields encephalitogenic peptides and its loss has been found to cause structural alteration of the myelin sheath. This suggests that MBP degradation is an initial step in the breakdown of myelin in demyelinating diseases. A calcium-activated neutral proteinase (calpain), which degrades MBP, was found to increase in activity in MS tissue and cerebrospinal fluid (CSF), and its presence in myelin suggests that myelin may be autodigested in demyelinating disease. The source of increased proteinase activity has been indicated as macrophages, lymphocytes, and proliferative astrocytes (reactive cells). Increased proteinase activity is found in Schwann cells in Wallerian degeneration, and the presence of calpain in myelin-forming oligodendrocytes and Schwann cells suggests that these cells are likely sources of degradative enzymes. The involvement of proteolytic enzymes in the mechanism of myelin breakdown indicates the possible intervention with proteinase inhibitors for beneficial effect.
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PMID:Pathogenesis of myelin breakdown in demyelinating diseases: role of proteolytic enzymes. 138 94

The degradation of myelin proteins has been implicated in destabilization of the myelin sheath in autoimmune demyelinating diseases such as multiple sclerosis (MS). In order to investigate the role of calcium-activated neutral proteinase (calpain), which degrades myelin proteins, the activity and expression (translational and transcriptional) of this enzyme were examined in spinal cords of Lewis rats with experimental allergic encephalomyelitis (EAE), an animal model of MS. In addition to calpain, the translational expression of calpastatin (endogenous inhibitor of calpain) and extent of neurofilament (NFP) and myelin protein degradation were evaluated via Western blotting in controls and rats with EAE. The transcriptional expression of millicalpain, microcalpain, and calpastatin as examined by RT-PCR was not significantly increased in EAE. However, calpain translational expression was increased by 206. 5% while the levels of 68 kDa NFP and myelin-associated glycoprotein were decreased by 42.9 and 39.7%, respectively, in animals with EAE compared to controls. Calpastatin isoforms (180, 110, 80, and 68 kDa) were significantly increased in EAE as well. The findings of increased activity and translational expression of calpain in EAE suggest a major role for this enzyme in myelinolysis associated with autoimmune demyelinating diseases.
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PMID:Upregulation of calpain activity and expression in experimental allergic encephalomyelitis: a putative role for calpain in demyelination. 963 May 23

Since calcium-activated neutral proteinase (calpain) activity and expression are significantly increased in activated glial/inflammatory cells in the central nervous system of animals with autoimmune demyelinating diseases, this enzyme may also play a role in peripheral organ systems in these diseases. In this study, the activity and expression of calpain and the endogenous inhibitor, calpastatin, were evaluated at transcriptional and translational levels in spleens of Lewis rats with acute experimental allergic encephalomyelitis (EAE) prior to the onset of clinical symptoms. Calpain activity and translational expression were increased by 475.5% and 44.3% respectively, on day 4 post-induction in adjuvant controls and animals with EAE. These levels remained elevated compared to normal controls on days 8 and 12. Calpastatin translational expression was similarly increased at these time points although transcriptional expression was not significantly altered at any time following induction of EAE. Likewise, transcriptional expression of mu-calpain was unchanged following induction, while small increases in m-calpain transcriptional expression were observed on days 2 and 8. Most calpain expression was observed in activated splenic macrophages at day 8 post-induction even though activated T cells were also calpain positive. In spinal cords of animals with EAE, calpain expression was significantly increased in rats with severe disease compared to those exhibiting only mild symptoms at day 12 post-induction. Thus, prior to symptomatic EAE, increased calpain activity and expression in peripheral lymphoid organs may play an important role in T cell migration and subsequent disease progression.
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PMID:Calpain activity and expression are increased in splenic inflammatory cells associated with experimental allergic encephalomyelitis. 1049 71

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.
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PMID:A putative mechanism of demyelination in multiple sclerosis by a proteolytic enzyme, calpain. 1050 Feb 3