@article{34a1c87f1fb148c99d849b10414ba359,
title = "Cytosolic calcium regulates cytoplasmic accumulation of tdp-43 through calpain-a and importin α3",
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.",
author = "Park, \{Jeong Hyang\} and Chung, \{Chang Geon\} and Park, \{Sung Soon\} and Davin Lee and Kim, \{Kyung Min\} and Yeonjin Jeong and Kim, \{Eun Seon\} and Cho, \{Jae Ho\} and Jeon, \{Yu Mi\} and Kim, \{Hyung Jun\} and Daehee Hwang and Lee, \{Sung Bae\} and Shen, \{Che Kun James\}",
note = "Funding Information: We thank the Bloomington Drosophila Stock Center, the Vienna Drosophila Resource Center and Bangalore Fly Resource Center for fly stocks. We thank Yuh Nung Jan (UCSF), Barry Ganetzky (Uni-versity of Wisconsin-Madison), Aaron Voigt (University Hospital, RWTH Aachen University), Brian D McCabe (EPFL) and Magalie Lecourtois (University of Rouen) for providing precious resources. This work was supported by Basic Science Research Program through the National Research Foundation of Korea, funded by the Ministry of Science and Information and Communications Technology (ICT) (2018R1A2B6001607, 2019R1A4A1024278); the Development of Platform Technology for Innovative Medical Measurements Program from the Korea Research Institute of Standards and Science Grant (KRISS-2019-GP2019-0018); KBRI basic research program through Korea Brain Research Institute funded by Ministry of Science and ICT (20-BR-04?02) (to SB Lee); and Institute for Basic Science Grant (IBS-R013-A1) funded by the Ministry of Science and ICT (to D Hwang). Additional information Funding Funder Grant reference number Author Ministry of science and ICT 2018R1A2B6001607 Sung Bae Lee Ministry of science and ICT 2019R1A4A1024278 Sung Bae Lee Korea Research Institute of Standards and Science KRISS-2019-GP2019-0018 Sung Bae Lee Ministry of Science and ICT 20-BR-04-02 Sung Bae Lee Ministry of Science and ICT IBS-R013-A1 Daehee Hwang. Funding Information: We thank the Bloomington Drosophila Stock Center, the Vienna Drosophila Resource Center and Bangalore Fly Resource Center for fly stocks. We thank Yuh Nung Jan (UCSF), Barry Ganetzky (University of Wisconsin-Madison), Aaron Voigt (University Hospital, RWTH Aachen University), Brian D McCabe (EPFL) and Magalie Lecourtois (University of Rouen) for providing precious resources. This work was supported by Basic Science Research Program through the National Research Foundation of Korea, funded by the Ministry of Science and Information and Communications Technology (ICT) (2018R1A2B6001607, 2019R1A4A1024278); the Development of Platform Technology for Innovative Medical Measurements Program from the Korea Research Institute of Standards and Science Grant (KRISS-2019-GP2019-0018); KBRI basic research program through Korea Brain Research Institute funded by Ministry of Science and ICT (20-BR-04–02) (to SB Lee); and Institute for Basic Science Grant (IBS-R013-A1) funded by the Ministry of Science and ICT (to D Hwang). Publisher Copyright: {\textcopyright} Park et al.",
year = "2020",
month = dec,
doi = "10.7554/eLife.60132",
language = "English",
volume = "9",
pages = "1--31",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications Ltd",
}