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.
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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.
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
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