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Pharmacological inhibition of MALT1 protease activity protects mice in a mouse model of multiple sclerosis

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Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
Abstract
Background: The paracaspase mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is crucial for lymphocyte activation through signaling to the transcription factor NF-kappa B. Besides functioning as a scaffold signaling protein, MALT1 also acts as a cysteine protease that specifically cleaves a number of substrates and contributes to specific T cell receptor-induced gene expression. Recently, small molecule inhibitors of MALT1 proteolytic activity were identified and shown to have promising anticancer properties in subtypes of B cell lymphoma. However, information on the therapeutic potential of small compound inhibitors that target MALT1 protease activity in autoimmunity is still lacking. Methods: The present study aimed to elucidate whether MALT1 protease inhibitors are also useful in the treatment of lymphocyte-mediated autoimmune pathologies such as multiple sclerosis (MS). For this, we studied the therapeutic potential of a recently identified inhibitor of MALT1 protease activity, the phenothiazine derivative mepazine, in the context of experimental autoimmune encephalomyelitis (EAE), the main animal model for MS. Results: We demonstrate that administration of mepazine prophylactically or after disease onset, can attenuate EAE. Importantly, while complete absence of MALT1 affects the differentiation of regulatory T (Treg) cells in vivo, the MALT1 protease inhibitor mepazine did not affect Treg development. Conclusions: Altogether, these data indicate that small molecule inhibitors of MALT1 not only hold great promise for the treatment of B cell lymphomas but also for autoimmune disorders such as MS.
Keywords
A20, IMMUNE, LYMPHOMA, CLEAVAGE, ACTIVATION, ABC-DLBCL, PARACASPASE MALT1, AUTOIMMUNE-MEDIATED DEMYELINATION, NF-KAPPA-B, demyelination, mepazine, MALT1, experimental autoimmune encephalomyelitis, multiple sclerosis

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Citation

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Chicago
Mc Guire, Conor, Lynn Elton, Peter Wieghofer, Jens Staal, Sofie Voet, Annelies Demeyer, Daniel Nagel, et al. 2014. “Pharmacological Inhibition of MALT1 Protease Activity Protects Mice in a Mouse Model of Multiple Sclerosis.” Journal of Neuroinflammation 11.
APA
Mc Guire, C., Elton, L., Wieghofer, P., Staal, J., Voet, S., Demeyer, A., Nagel, D., et al. (2014). Pharmacological inhibition of MALT1 protease activity protects mice in a mouse model of multiple sclerosis. JOURNAL OF NEUROINFLAMMATION, 11.
Vancouver
1.
Mc Guire C, Elton L, Wieghofer P, Staal J, Voet S, Demeyer A, et al. Pharmacological inhibition of MALT1 protease activity protects mice in a mouse model of multiple sclerosis. JOURNAL OF NEUROINFLAMMATION. 2014;11.
MLA
Mc Guire, Conor, Lynn Elton, Peter Wieghofer, et al. “Pharmacological Inhibition of MALT1 Protease Activity Protects Mice in a Mouse Model of Multiple Sclerosis.” JOURNAL OF NEUROINFLAMMATION 11 (2014): n. pag. Print.
@article{5685214,
  abstract     = {Background: The paracaspase mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is crucial for lymphocyte activation through signaling to the transcription factor NF-kappa B. Besides functioning as a scaffold signaling protein, MALT1 also acts as a cysteine protease that specifically cleaves a number of substrates and contributes to specific T cell receptor-induced gene expression. Recently, small molecule inhibitors of MALT1 proteolytic activity were identified and shown to have promising anticancer properties in subtypes of B cell lymphoma. However, information on the therapeutic potential of small compound inhibitors that target MALT1 protease activity in autoimmunity is still lacking.
Methods: The present study aimed to elucidate whether MALT1 protease inhibitors are also useful in the treatment of lymphocyte-mediated autoimmune pathologies such as multiple sclerosis (MS). For this, we studied the therapeutic potential of a recently identified inhibitor of MALT1 protease activity, the phenothiazine derivative mepazine, in the context of experimental autoimmune encephalomyelitis (EAE), the main animal model for MS.
Results: We demonstrate that administration of mepazine prophylactically or after disease onset, can attenuate EAE. Importantly, while complete absence of MALT1 affects the differentiation of regulatory T (Treg) cells in vivo, the MALT1 protease inhibitor mepazine did not affect Treg development.
Conclusions: Altogether, these data indicate that small molecule inhibitors of MALT1 not only hold great promise for the treatment of B cell lymphomas but also for autoimmune disorders such as MS.},
  articleno    = {124},
  author       = {Mc Guire, Conor and Elton, Lynn and Wieghofer, Peter and Staal, Jens and Voet, Sofie and Demeyer, Annelies and Nagel, Daniel and Krappmann, Daniel and Prinz, Marco and Beyaert, Rudi and van Loo, Geert},
  issn         = {1742-2094},
  journal      = {JOURNAL OF NEUROINFLAMMATION},
  keyword      = {A20,IMMUNE,LYMPHOMA,CLEAVAGE,ACTIVATION,ABC-DLBCL,PARACASPASE MALT1,AUTOIMMUNE-MEDIATED DEMYELINATION,NF-KAPPA-B,demyelination,mepazine,MALT1,experimental autoimmune encephalomyelitis,multiple sclerosis},
  language     = {eng},
  pages        = {12},
  title        = {Pharmacological inhibition of MALT1 protease activity protects mice in a mouse model of multiple sclerosis},
  url          = {http://dx.doi.org/10.1186/1742-2094-11-124},
  volume       = {11},
  year         = {2014},
}

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