Characterization of the regulatory mechanism underlying nucleocytoplasmic transport of TDP-43 proteins in neurons

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. In this study, I found that TDP-43 shows cell type-dependent variation in its localization and can undergo dynamic and reversible changes in its localization during development, one of the major cellular events, in Drosophila sensory neurons. Furthermore, I identified cytosolic calcium as a key cellular factor controlling NCT of TDP-43 via FRAP and optogenetics. 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.