Park, J.H., Chung, C.G., Park, S.S., Lee, D., Kim, K.M., Jeong, Y., Kim, E.S., Cho, J.H., Jeon, Y.M., Shen, C.J., Kim, H.J., Hwang, D., Lee, S.B. (2020). Cytosolic calcium regulates cytoplasmic accumulation of TDP-43 through Calpain-A and Importin α3.  eLife 9(): e60132.

FBrf0247671

Research paper

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.

PMC7748415 (PMC) (EuropePMC)