Nuclear TDP-43 regulates Golgi outposts in Drosophila neurons

Abstract

TDP-43 is a heterogeneous nuclear ribonucleoprotein (HnRNP) whose abnormal clearance in the nucleus and aberrant accumulation in the cytoplasm is frequently observed in several neurodegenerative diseases such as ALS/FTD. Although molecular functions of TDP-43, such as mRNA processing, have been well characterized, its physiological role in neurons remains unclear. In this study, we elucidated the novel role of dTDP-43 in the formation of Golgi outposts (GOPs) in dendrites. We found that the nuclear localization of dTDP-43 determines the number of GOPs in Drosophila neurons. Loss-of-function genetic screening of previously characterized co-factors of dTDP-43 nuclear function showed that two pre-mRNA splicing partners, Hrb27C and Hrb98DE, are associated with dTDP-43-induced increase of GOPs. Additional loss-of-function genetic screening of NGS-derived differentially expressed genes (DEGs) in dTDP-43 overexpressed brain further identified several specific Rab GTPases and their interactors as effectors of this novel role of dTDP-43. Finally, we found that late endo-lysosomal compartments and plasma membrane supply were also increased following increased GOPs in dendrites of dTDP-43-expressing neurons. Taken together, our results suggest that TDP-43 contributes to the neuronal local membrane trafficking through the regulation of GOPs.