TBPH/TDP-43 modulates translation of Drosophila futsch mRNA through an UG-rich sequence within its 5′UTR

Nuclear factor TDP-43 is an evolutionarily conserved multifunctional RNA-binding protein associated with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). In recent years, Drosophila models of ALS based on TDP-43 knockdown/overexpression have allowed to find several connections with disease. Among these, we have previously described that silencing the expression of its fly ortholog (TBPH) can alter the expression of the neuronal microtubule-associated protein Futsch leading to alterations of neuromuscular junction (NMJ) organization. In particular, TBPH knocked out flies displayed a significant reduction of Futsch protein levels, although minimal variation in the futsch mRNA content was observed. These conclusions were recently validated in an independent study. Together, these observations strongly support the hypothesis that TBPH might regulate the translation of futsch mRNA. However, the mechanism of TBPH interference in futsch mRNA translation is still unknown. In this work, we use EMSA experiments coupled with RNA-protein co-immunprecipitations and luciferase assays to show that TBPH interacts with a stretch of UG within the 5′UTR of futsch mRNA and translation is positively modulated by this binding. Most importantly, this function is also conserved in human TDP-43. This result can therefore represent the first step in elucidating the relationship between TDP-43, protein translation, and eventual disease onset or progression.