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

Jiayi Li, Wilaiwan Wisessmith Durose, Junko Ito, Akiyoshi Kakita, Yohei Iguchi, Masahisa Katsuno, Kazuo Kunisawa, Takeshi Shimizu, Kazuhiro Ikenaka

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)2070-2090
Number of pages21
JournalJournal of Neurochemistry
Volume157
Issue number6
Early online dateSep 18 2020
DOIs
StatePublished - Jun 2021

Bibliographical note

Funding Information:
This work was funded by a Grant-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 by the Thailand Research Fund under the Royal Golden Jubilee-Ph.D. Scholarship and Mahidol University to WW and BC. The CysF-STOP-tetO, Iba-mtTA, MLC-mtTA, and PLP4e/- mice were provided by Takahiro Shimizu in the Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki, Japan, and Kenji Tanaka in the Department of Neuropsychiatry, Keio University, Tokyo, Japan. The human tissue was provided by the Collaborative Research Project of the Brain Research Institute,?Niigata University. We are grateful for the technical assistance provided by Hirokazu Hashimoto from the Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki, Japan. All experiments were conducted in compliance with the ARRIVE guidelines.

Funding Information:
This work was funded by a Grant‐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 by the Thailand Research Fund under the Royal Golden Jubilee‐Ph.D. Scholarship and Mahidol University to WW and BC. The CysF‐STOP‐tetO, Iba‐mtTA, MLC‐mtTA, and mice were provided by Takahiro Shimizu in the Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki, Japan, and Kenji Tanaka in the Department of Neuropsychiatry, Keio University, Tokyo, Japan. The human tissue was provided by the Collaborative Research Project of the Brain Research Institute, Niigata University. We are grateful for the technical assistance provided by Hirokazu Hashimoto from the Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki, Japan. PLP 4e/‐

Publisher Copyright:
© 2020 International Society for Neurochemistry

Keywords

  • ELAVL-1
  • cystatin F
  • demyelinating diseases
  • gene expression regulation
  • miR29a
  • remyelination
  • NIH 3T3 Cells
  • Humans
  • Mice, Inbred C57BL
  • Middle Aged
  • Cystatins/genetics
  • Male
  • Mice, Transgenic
  • Multiple Sclerosis/genetics
  • Biomarkers, Tumor/genetics
  • Animals
  • Female
  • Mice, Inbred DBA
  • RNA Processing, Post-Transcriptional/physiology
  • Remyelination/physiology
  • Aged
  • Mice

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Journal Article

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