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

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.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

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.

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.

Metrics

  • 3,386
    views
  • 538
    downloads
  • 22
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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
  13. Sung Bae Lee
(2020)
Cytosolic calcium regulates cytoplasmic accumulation of TDP-43 through Calpain-A and Importin α3
eLife 9:e60132.
https://doi.org/10.7554/eLife.60132

Share this article

https://doi.org/10.7554/eLife.60132

Further reading

    1. Neuroscience
    Yi-Yun Ho, Qiuwei Yang ... Melissa R Warden
    Research Article

    The infralimbic cortex (IL) is essential for flexible behavioral responses to threatening environmental events. Reactive behaviors such as freezing or flight are adaptive in some contexts, but in others a strategic avoidance behavior may be more advantageous. IL has been implicated in avoidance, but the contribution of distinct IL neural subtypes with differing molecular identities and wiring patterns is poorly understood. Here, we study IL parvalbumin (PV) interneurons in mice as they engage in active avoidance behavior, a behavior in which mice must suppress freezing in order to move to safety. We find that activity in inhibitory PV neurons increases during movement to avoid the shock in this behavioral paradigm, and that PV activity during movement emerges after mice have experienced a single shock, prior to learning avoidance. PV neural activity does not change during movement toward cued rewards or during general locomotion in the open field, behavioral paradigms where freezing does not need to be suppressed to enable movement. Optogenetic suppression of PV neurons increases the duration of freezing and delays the onset of avoidance behavior, but does not affect movement toward rewards or general locomotion. These data provide evidence that IL PV neurons support strategic avoidance behavior by suppressing freezing.

    1. Neuroscience
    David C Williams, Amanda Chu ... Michael A McDannald
    Research Advance Updated

    Recognizing and responding to threat cues is essential to survival. Freezing is a predominant threat behavior in rats. We have recently shown that a threat cue can organize diverse behaviors beyond freezing, including locomotion (Chu et al., 2024). However, that experimental design was complex, required many sessions, and had rats receive many foot shock presentations. Moreover, the findings were descriptive. Here, we gave female and male Long Evans rats cue light illumination paired or unpaired with foot shock (eight total) in a conditioned suppression setting using a range of shock intensities (0.15, 0.25, 0.35, or 0.50 mA). We found that conditioned suppression was only observed at higher foot shock intensities (0.35 mA and 0.50 mA). We constructed comprehensive temporal ethograms by scoring 22,272 frames across 12 behavior categories in 200-ms intervals around cue light illumination. The 0.50 mA and 0.35 mA shock-paired visual cues suppressed reward seeking, rearing, and scaling, as well as light-directed rearing and light-directed scaling. These shock-paired visual cues further elicited locomotion and freezing. Linear discriminant analyses showed that ethogram data could accurately classify rats into paired and unpaired groups. Using complete ethogram data produced superior classification compared to behavior subsets, including an immobility subset featuring freezing. The results demonstrate diverse threat behaviors – in a short and simple procedure – containing sufficient information to distinguish the visual fear conditioning status of individual rats.