Increased calpain expression in activated glial and inflammatory cells in experimental allergic encephalomyelitis

Shields, Donald C.; Tyor, William R.; Deibler, Gladys E.; Hogan, Edward L.; Banik, Naren L.

doi:10.1073/pnas.95.10.5768

Cited by 75 publications

(48 citation statements)

References 36 publications

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“…Recent studies have demonstrated increased calpain activity and translational expression in the optic nerves and spinal cords of Lewis rats with acute EAE, the corresponding MS animal model (7,(34)(35)(36). In EAE, calpain and calpastatin transcriptional expression were not altered significantly whereas calpain translational expression was up-regulated in glial͞inflammatory cells upon activation.…”

Section: Discussionmentioning

confidence: 99%

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

Shields

Schaecher²,

Saido³

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

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151

111

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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 calpainspecific 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 immunof luorescent 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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Section: Discussionmentioning

confidence: 99%

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

Shields

Schaecher²,

Saido³

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

151

111

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“…The regulatory subunit is common to both calpains and requires sequential cleavage events to convert it from the inactive 28-kDa precursor into the active 21-kDa form upon Ca 2ϩ addition. Calpains are activated by many apoptotic and necrotic stimuli, particularly those that alter Ca 2ϩ levels in the cell and their activation often lies upstream of caspase activation (31)(32)(33)(34)(35)(36)(37)(38).…”

Section: Huntington's Disease (Hd)mentioning

confidence: 99%

Inhibition of Calpain Cleavage of Huntingtin Reduces Toxicity

Gafni

Hermel

Young

et al. 2004

Journal of Biological Chemistry

244

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Huntington's disease (HD) is a neurodegenerative disorder caused by a polyglutamine (polyQ) tract expansion near the N terminus of huntingtin (Htt). Proteolytic processing of mutant Htt and abnormal calcium signaling may play a critical role in disease progression and pathogenesis. Recent work indicates that calpains may participate in the increased and/or altered patterns of Htt proteolysis leading to the selective toxicity observed in HD striatum. Here, we identify two calpain cleavage sites in Htt and show that mutation of these sites renders the polyQ expanded Htt less susceptible to proteolysis and aggregation, resulting in decreased toxicity in an in vitro cell culture model. In addition, we found that calpain-and caspase-derived Htt fragments preferentially accumulate in the nucleus without the requirement of further cleavage into smaller fragments. Calpain family members, calpain-1, -5, -7, and -10, have increased levels or are activated in HD tissue culture and transgenic mouse models, suggesting they may play a key role in Htt proteolysis and disease pathology. Interestingly, calpain-1, -5, -7, and -10 localize to the cytoplasm and the nucleus, whereas the activated forms of calpain-7 and -10 are found only in the nucleus. These results support the role of calpain-derived Htt fragmentation in HD and suggest that aberrant activation of calpains may play a role in HD pathogenesis.

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“…Proteases (acidic and neutral) that degrade these proteins and cytoskeletal proteins have been implicated in myelinolysis and cell death Shields and Banik, 1998b). Increased activity and expression of the Ca 2+ -activated protease calpain has been found in tissue of patients with MS as well as in the corresponding animal model, experimental allergic encephalomyelitis (EAE) (Banik, 1992;Cuzner et al, 1975;Guyton et al, 2005;Hassen et al, 2006;Shields and Banik, 1998a;Shields et al, 1998;Smith, 1977).…”

Section: Introductionmentioning

confidence: 99%

Increased calpain correlates with Th1 cytokine profile in PBMCs from MS patients

Imam

Guyton

Haque

et al. 2007

Journal of Neuroimmunology

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Multiple sclerosis (MS) is a devastating autoimmune demyelinating disease of the CNS. This study investigated whether expression and activity of the calcium-activated protease calpain correlated with Th1/Th2 dysregulation in MS patients during states of relapse and remission. Calpain expression and activity were significantly increased in peripheral blood mononuclear cells (PBMCs) from MS patients, compared to controls, with the highest expression and activity noted during relapse. Th1 cytokines were highest and Th2 cytokines were lowest in MS patients during relapse. Treatment with calpain inhibitor, calpeptin, decreased Th1 cytokines in PBMCs from MS patients. Calpain inhibitor also reduced degradation of myelin basic protein (MBP) by inhibiting the calpain secreted from MBPspecific T cells. Taken together, these results suggested calpain involvement in Th1/Th2 dysregulation in MS patients.

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Increased calpain expression in activated glial and inflammatory cells in experimental allergic encephalomyelitis

Cited by 75 publications

References 36 publications

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

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

Inhibition of Calpain Cleavage of Huntingtin Reduces Toxicity

Increased calpain correlates with Th1 cytokine profile in PBMCs from MS patients

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