@article {10.7554/eLife.60132, article_type = {journal}, title = {Cytosolic calcium regulates cytoplasmic accumulation of TDP-43 through Calpain-A and Importin 3}, author = {Park, Jeong Hyang and Chung, Chang Geon and Park, Sung Soon and Lee, Davin and Kim, Kyung Min and Jeong, Yeonjin and Kim, Eun Seon and Cho, Jae Ho and Jeon, Yu-Mi and Shen, C-K James and Kim, Hyung-Jun and Hwang, Daehee and Lee, Sung Bae}, editor = {Shim, Jiwon and VijayRaghavan, K and Tibbetts, Randal S}, volume = 9, year = 2020, month = {dec}, pub_date = {2020-12-11}, pages = {e60132}, citation = {eLife 2020;9:e60132}, doi = {10.7554/eLife.60132}, url = {https://doi.org/10.7554/eLife.60132}, 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 \textit{Drosophila} sensory neurons during development. Genetic and immunohistochemical analyses identified the cytosolic calcium-Calpain-A-Importin 3 pathway as a regulatory mechanism underlying NCT of TDP-43. In \textit{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 3 pathway as a potential therapeutic target of ALS.}, keywords = {TDP-43, nucleocytoplasmic transport, amyotrophic lateral sclerosis, calcium, calpain, \textit{Drosophila}}, journal = {eLife}, issn = {2050-084X}, publisher = {eLife Sciences Publications, Ltd}, } 管家婆期期准免费资料精选