TY - JOUR TI - Cytosolic calcium regulates cytoplasmic accumulation of TDP-43 through Calpain-A and Importin 3 AU - Park, Jeong Hyang AU - Chung, Chang Geon AU - Park, Sung Soon AU - Lee, Davin AU - Kim, Kyung Min AU - Jeong, Yeonjin AU - Kim, Eun Seon AU - Cho, Jae Ho AU - Jeon, Yu-Mi AU - Shen, C-K James AU - Kim, Hyung-Jun AU - Hwang, Daehee AU - Lee, Sung Bae A2 - Shim, Jiwon A2 - VijayRaghavan, K A2 - Tibbetts, Randal S VL - 9 PY - 2020 DA - 2020/12/11 SP - e60132 C1 - eLife 2020;9:e60132 DO - 10.7554/eLife.60132 UR - https://doi.org/10.7554/eLife.60132 AB - 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 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 3 pathway as a potential therapeutic target of ALS. KW - TDP-43 KW - nucleocytoplasmic transport KW - amyotrophic lateral sclerosis KW - calcium KW - calpain KW - Drosophila JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER - 管家婆期期准免费资料精选