1. Neuroscience
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Cytosolic calcium regulates cytoplasmic accumulation of TDP-43 through Calpain-A and Importin α3

  1. Jeong Hyang Park
  2. Chang Geon Chung
  3. Sung Soon Park
  4. Davin Lee
  5. Kyung Min Kim
  6. Yeonjin Jeong
  7. Eun Seon Kim
  8. Jae Ho Cho
  9. Yu-Mi Jeon
  10. C-K James Shen
  11. Hyung-Jun Kim
  12. Daehee Hwang  Is a corresponding author
  13. Sung Bae Lee  Is a corresponding author
  1. DGIST, Republic of Korea
  2. Seoul National University, Republic of Korea
  3. KBRI, Republic of Korea
  4. Academia Sinica, Taiwan
Research Article
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Cite this article as: eLife 2020;9:e60132 doi: 10.7554/eLife.60132

Abstract

Cytoplasmic accumulation of TDP-43 in motor neurons is the most prominent pathological feature in amyotrophic lateral sclerosis (ALS). A feedback cycle between nucleocytoplasmic transport (NCT) defect and TDP-43 aggregation was shown to contribute to accumulation of TDP-43 in the cytoplasm. However, little is known about cellular factors that can control the activity of NCT, thereby affecting TDP-43 accumulation in the cytoplasm. Here, we identified via FRAP and optogenetics cytosolic calcium as a key cellular factor controlling NCT of TDP-43. Dynamic and reversible changes in TDP-43 localization were observed in Drosophila sensory neurons during development. Genetic and immunohistochemical analyses identified the cytosolic calcium-Calpain-A-Importin α3 pathway as a regulatory mechanism underlying NCT of TDP-43. In C9orf72 ALS fly models, upregulation of the pathway activity by increasing cytosolic calcium reduced cytoplasmic accumulation of TDP-43 and mitigated behavioral defects. Together, these results suggest the calcium-Calpain-A-Importin α3 pathway as a potential therapeutic target of ALS.

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Author details

  1. Jeong Hyang Park

    Brain and Cognitive Sciences, DGIST, Daegu, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7392-8366
  2. Chang Geon Chung

    Brain & Cognitive Sciences, DGIST, Daegu, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8155-4926
  3. Sung Soon Park

    Brain and Cognitive Sciences, DGIST, Daegu, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  4. Davin Lee

    Brain and Cognitive Sciences, DGIST, Daegu, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  5. Kyung Min Kim

    School of Biological Sciences, Seoul National University, Seoul, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  6. Yeonjin Jeong

    Brain and Cognitive Sciences, DGIST, Daegu, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  7. Eun Seon Kim

    Dementia research group, KBRI, Daegu, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  8. Jae Ho Cho

    Brain and Cognitive Sciences, DGIST, Daegu, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  9. Yu-Mi Jeon

    Dementia research group, KBRI, Daegu, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  10. C-K James Shen

    Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan
    Competing interests
    The authors declare that no competing interests exist.
  11. Hyung-Jun Kim

    Dementia research group, KBRI, Daegu, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  12. Daehee Hwang

    School of Biological Sciences, Seoul National University, Seoul, Republic of Korea
    For correspondence
    daehee@snu.ac.kr
    Competing interests
    The authors declare that no competing interests exist.
  13. Sung Bae Lee

    Brain and Cognitive Sciences, DGIST, Daegu, Republic of Korea
    For correspondence
    sblee@dgist.ac.kr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8980-6769

Funding

Ministry of Science and ICT, South Korea (2018R1A2B6001607)

  • Sung Bae Lee

Ministry of Science and ICT, South Korea (2019R1A4A1024278)

  • Sung Bae Lee

Korea Research Institute of Standards and Science (KRISS-2019-GP2019-0018)

  • Sung Bae Lee

Ministry of Science and ICT, South Korea (20-BR-04-02)

  • Sung Bae Lee

Ministry of Science and ICT, South Korea (IBS-R013-A1)

  • Daehee Hwang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Jiwon Shim, Hanyang University, Republic of Korea

Publication history

  1. Received: June 17, 2020
  2. Accepted: December 9, 2020
  3. Accepted Manuscript published: December 11, 2020 (version 1)

Copyright

? 2020, Park et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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