Exploring the factors underlying remyelination arrest by studying the post‐transcriptional regulatory mechanisms of cystatin F gene. Issue 6 (1st October 2020)

• Record Type: Journal Article
• Authors: Li, Jiayi; Durose, Wilaiwan Wisessmith; Ito, Junko; Kakita, Akiyoshi; Iguchi, Yohei; Katsuno, Masahisa; Kunisawa, Kazuo; Shimizu, Takeshi; Ikenaka, Kazuhiro
• Is Part Of: Journal of neurochemistry. Volume 157:Issue 6(2021)
• Page Start: 2070
• Page End: 2090
• Publication Date: 2020-10-01
• Subjects: cystatin F -- demyelinating diseases -- ELAVL‐1 -- gene expression regulation -- miR29a -- remyelination; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.15190
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: Remyelination plays an important role in determining the fate of demyelinating disorders. However, it is arrested during chronic disease states. Cystatin F, a papain‐like lysosomal cysteine proteinase inhibitor, is a crucial regulator of demyelination and remyelination. Using hemizygous proteolipid protein transgenic 4e ( PLP 4e/‐ ) mice, an animal model of chronic demyelination, we found that cystatin F mRNA expression was induced at 2.5 months of age and up‐regulated in the early phase of demyelination, but significantly decreased in the chronic phase. We next investigated cystatin F regulatory factors as potential mechanisms of remyelination arrest in chronic demyelinating disorders. We used the CysF‐STOP‐tetO::Iba‐mtTA mouse model, in which cystatin F gene expression is driven by the tetracycline operator. Interestingly, we found that forced cystatin F mRNA over‐expression was eventually decreased. Our findings show that cystatin F expression is modulated post‐transcriptionally. We next identified embryonic lethal, abnormal vision, drosophila like RNA‐binding protein 1 (ELAVL‐1), and miR29a as cystatin F mRNA stabilizing and destabilizing factors, respectively. These roles were confirmed in vitro in NIH3T3 cells. Using postmortem plaque samples from human multiple sclerosis patients, we also confirmed that ELAVL‐1 expression was highly correlated with the previously reported expression pattern of cystatin F. These data indicate the important roles of ELAVL‐1 and miR29a in regulating cystatin F expression. Furthermore, they provide new insights into potential therapeutic targets for demyelinating disorders. Abstract : Remyelination is important in determining the fate of demyelinating disorders. However, it is arrested during chronic disease states. We found that mRNA expression of cystatin F, a papain‐like lysosomal cysteine proteinase inhibitor and regulator of de‐ and remyelination, was induced in mice at 2.5 months of age and up‐regulated in the early phase of demyelination, but significantly decreased in the chronic phase. We also identified embryonic lethal, abnormal vision, drosophila like RNA‐binding protein 1 (ELAVL‐1) and miR29a as cystatin F mRNA stabilizing and destabilizing factors, respectively. Using postmortem plaque samples from human multiple sclerosis patients, we also confirmed that ELAVL‐1 expression was highly correlated with the previously reported expression pattern of cystatin F. These data indicate the important roles of ELAVL‐1 and miR29a in regulating cystatin F expression and provide new insights into potential therapeutic targets for demyelinating disorders.