Exploring the factors underlying remyelination arrest by studying the post-transcriptional regulatory mechanisms of cystatin F gene.

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 (PLP4e/- ) 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.

• Authors: Jiayi Li, Wilaiwan Wisessmith Durose, Junko Ito, Akiyoshi Kakita, Yohei Iguchi, Masahisa Katsuno, Kazuo Kunisawa, Takeshi Shimizu, Kazuhiro Ikenaka
• Journal: Journal of neurochemistry (J Neurochem) Vol. 157 Issue 6 Pg. 2070-2090 (06 2021) ISSN: 1471-4159 [Electronic] England
• PMID: 32947653 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 International Society for Neurochemistry.

Chemical References

• Biomarkers, Tumor
• CST7 protein, human
• Cystatins
• cystatin F, mouse

Topics

• Aged
• Animals
• Biomarkers, Tumor (genetics, metabolism)
• Cystatins (genetics, metabolism)
• Female
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Inbred DBA
• Mice, Transgenic
• Middle Aged
• Multiple Sclerosis (genetics, metabolism)
• NIH 3T3 Cells
• RNA Processing, Post-Transcriptional (physiology)
• Remyelination (physiology)