Cytosolic calcium regulates cytoplasmic accumulation of TDP-43 through Calpain-A and Importin α3
- DGIST, Republic of Korea
- Seoul National University, Republic of Korea
- KBRI, Republic of Korea
- 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
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
- Jiwon Shim, Hanyang University, Republic of Korea
Version history
- Received: June 17, 2020
- Accepted: December 9, 2020
- Accepted Manuscript published: December 11, 2020 (version 1)
- Version of Record published: December 18, 2020 (version 2)
- 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.
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Cytosolic calcium regulates cytoplasmic accumulation of TDP-43 through Calpain-A and Importin α3
eLife 9:e60132.
https://doi.org/10.7554/eLife.60132
