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.
Bibliographical noteFunding Information:
This work was supported by Grants-in-Aid for Scientific Research on Innovative Areas: ?Foundation of Synapse and Neurocircuit Pathology (23110521)?, Japan Society for the Promotion of Science (JSPS), ?Glial Assembly: a new regulatory machinery of brain function and disorders (25117001)? and ?Thailand Research Fund under the Royal Golden Jubilee-Ph.D. Scholarship and Mahidol University? to WW and BC. The activity assays were performed with help from Akio Suzumura and Tetsuya Mizuno in the Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Japan; Yasuo Uchiyama and Masato Koike in the School of Medicine, Juntendo University, Japan; and Masahiro Shibata in Niigata University, Japan. The southern blotting was performed with help from Maya Yamazaki (current affiliation: Niccole lab at the University of California San Francisco, USA). Electron microscopy analysis was performed with help from Katsutoshi Ogasawara and other staff at the Center for Electron Microscopy and Bio-Imaging Research, Iwate Medical University. The anti-cystatin F antibody was generously gifted from Colin Watts (Dundee University). This work was also supported by JSPS KAKENHI (25650181 and 25245069) to KT, a Grant-in-Aid for Strategic Medical Science Research for private university (No. S1491001, 2014-2018) from MEXT to YS.
- cysteine protease inhibitor