title: The balance between cathepsin C and cystatin F controls remyelination in the brain of Plp1-overexpressing mouse, a chronic demyelinating disease model.
abstract: In demyelinating diseases such as multiple sclerosis (MS), an imbalance between the demyelination and remyelination rates underlies the degenerative processes. Microglial activation is observed in demyelinating lesions; however, the molecular mechanism responsible for the homeostatic/environmental change remains elusive. We previously found that cystatin F (CysF), a cysteine protease inhibitor, is selectively expressed in microglia only in actively demyelinating/remyelinating lesions but ceases expression in chronic lesions, suggesting its role in remyelination. Here, we report the effects of manipulating the expression of CysF and cathepsin C (CatC), a key target of CysF, in a murine model of transgenic demyelinating disease, Plp4e/-. During the active remyelinating phase, both CysF knockdown (CysFKD) and microglial-selective CatC overexpression (CatCOE) showed a worsening of the demyelination in Plp4e/-transgenic mice. Conversely, during the chronic demyelinating phase, CatC knockdown (CatCKD) ameliorated the demyelination. Our results suggest that the balance between CatC and CysF expression controls the demyelination and remyelination process.
authors.affiliation: Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki, Japan.|Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhonpathom, Thailand.
authors.forename: Wilaiwan
authors.initials: W
authors.lastname: Wisessmith
authors.affiliation: Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki, Japan.|Department of Physiological Sciences, Graduate University for Advanced Studies (SOKENDAI), Okazaki, Japan.
authors.forename: Jiayi
authors.initials: J
authors.lastname: Li
authors.affiliation: Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Abe
authors.affiliation: Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakimura
authors.affiliation: Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhonpathom, Thailand.
authors.forename: Banthit
authors.initials: B
authors.lastname: Chetsawang
authors.affiliation: Department of Physiology, Iwate Medical University School of Dentistry, Iwate, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Sahara
authors.affiliation: Department of Physiology, Iwate Medical University School of Dentistry, Iwate, Japan.|Center for Electron Microscopy and Bio-Imaging Research, Iwate Medical University, Iwate, Japan.
authors.forename: Koujiro
authors.initials: K
authors.lastname: Tohyama
authors.affiliation: Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki, Japan.|Department of Neuropsychiatry, Keio University, Tokyo, Japan.
authors.forename: Kenji F
authors.initials: KF
authors.lastname: Tanaka
authors.affiliation: Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki, Japan.|Department of Physiological Sciences, Graduate University for Advanced Studies (SOKENDAI), Okazaki, Japan.
authors.forename: Kazuhiro
authors.identifier: 0000-0002-2983-2498
authors.initials: K
authors.lastname: Ikenaka
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D020789:Cathepsin C / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D015891:Cystatins / Q000235:genetics / Q000378:metabolism*; D003711:Demyelinating Diseases / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D018390:Gene Targeting; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D018991:Myelin Proteolipid Protein / Q000235:genetics / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D015891:Cystatins; D008840:Microfilament Proteins; D018991:Myelin Proteolipid Protein; C047516:Plp1 protein, mouse; D012333:RNA, Messenger; C550521:cystatin F, mouse; D020789:Cathepsin C; C533919:Ctsc protein, mouse
keywords: cysteine protease inhibitor; demyelination; microglia; remyelination