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Cytosolic calcium regulates cytoplasmic accumulation of TDP-43 through Calpain-A and Importin alpha 3

Authors
Park, Jeong HyangChung, Chang GeonPark, Sung SoonLee, DavinKim, Kyung MinJeong, YeonjinKim, Eun SeonCho, Jae HoJeon, Yu-MiShen, C-K JamesKim, Hyung-JunHwang, DaeheeLee, Sung Bae
Issue Date
Dec-2020
Publisher
ELIFE SCIENCES PUBLICATIONS LTD
Citation
ELIFE, v.9
Journal Title
ELIFE
Volume
9
URI
http://scholarworks.bwise.kr/kbri/handle/2023.sw.kbri/564
DOI
10.7554/eLife.60132
ISSN
2050-084X
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 alpha 3 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 a3 pathway as a potential therapeutic target of ALS.
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