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.

Reviewing Editor

  1. Jiwon Shim, Hanyang University, Republic of Korea

Version history

  1. Received: June 17, 2020
  2. Accepted: December 9, 2020
  3. Accepted Manuscript published: December 11, 2020 (version 1)
  4. Version of Record published: December 18, 2020 (version 2)
  5. Version of Record updated: December 30, 2020 (version 3)

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

  • 3,164
    views
  • 514
    downloads
  • 19
    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. Biochemistry and Chemical Biology
    2. Neuroscience
    Maximilian Nagel, Marco Niestroj ... Marc Spehr
    Research Article

    In most mammals, conspecific chemosensory communication relies on semiochemical release within complex bodily secretions and subsequent stimulus detection by the vomeronasal organ (VNO). Urine, a rich source of ethologically relevant chemosignals, conveys detailed information about sex, social hierarchy, health, and reproductive state, which becomes accessible to a conspecific via vomeronasal sampling. So far, however, numerous aspects of social chemosignaling along the vomeronasal pathway remain unclear. Moreover, since virtually all research on vomeronasal physiology is based on secretions derived from inbred laboratory mice, it remains uncertain whether such stimuli provide a true representation of potentially more relevant cues found in the wild. Here, we combine a robust low-noise VNO activity assay with comparative molecular profiling of sex- and strain-specific mouse urine samples from two inbred laboratory strains as well as from wild mice. With comprehensive molecular portraits of these secretions, VNO activity analysis now enables us to (i) assess whether and, if so, how much sex/strain-selective ‘raw’ chemical information in urine is accessible via vomeronasal sampling; (ii) identify which chemicals exhibit sufficient discriminatory power to signal an animal’s sex, strain, or both; (iii) determine the extent to which wild mouse secretions are unique; and (iv) analyze whether vomeronasal response profiles differ between strains. We report both sex- and, in particular, strain-selective VNO representations of chemical information. Within the urinary ‘secretome’, both volatile compounds and proteins exhibit sufficient discriminative power to provide sex- and strain-specific molecular fingerprints. While total protein amount is substantially enriched in male urine, females secrete a larger variety at overall comparatively low concentrations. Surprisingly, the molecular spectrum of wild mouse urine does not dramatically exceed that of inbred strains. Finally, vomeronasal response profiles differ between C57BL/6 and BALB/c animals, with particularly disparate representations of female semiochemicals.

    1. Neuroscience
    Kenta Abe, Yuki Kambe ... Tatsuo Sato
    Research Article

    Midbrain dopamine neurons impact neural processing in the prefrontal cortex (PFC) through mesocortical projections. However, the signals conveyed by dopamine projections to the PFC remain unclear, particularly at the single-axon level. Here, we investigated dopaminergic axonal activity in the medial PFC (mPFC) during reward and aversive processing. By optimizing microprism-mediated two-photon calcium imaging of dopamine axon terminals, we found diverse activity in dopamine axons responsive to both reward and aversive stimuli. Some axons exhibited a preference for reward, while others favored aversive stimuli, and there was a strong bias for the latter at the population level. Long-term longitudinal imaging revealed that the preference was maintained in reward- and aversive-preferring axons throughout classical conditioning in which rewarding and aversive stimuli were paired with preceding auditory cues. However, as mice learned to discriminate reward or aversive cues, a cue activity preference gradually developed only in aversive-preferring axons. We inferred the trial-by-trial cue discrimination based on machine learning using anticipatory licking or facial expressions, and found that successful discrimination was accompanied by sharper selectivity for the aversive cue in aversive-preferring axons. Our findings indicate that a group of mesocortical dopamine axons encodes aversive-related signals, which are modulated by both classical conditioning across days and trial-by-trial discrimination within a day.