Drosophila CG3303 is an essential endoribonuclease linked to TDP-43-mediated neurodegeneration

Laneve, Pietro; Piacentini, Lucia; Casale, Assunta Maria; Capauto, Davide; Gioia, Ubaldo; Cappucci, Ugo; Di Carlo, Valerio; Bozzoni, Irene; Di Micco, Patrizio; Morea, Veronica; Di Franco, Carmela Antonia; Caffarelli, Elisa

We unveiled a crucial role for DendoU in Drosophila nervous system physiology and pathology. Remarkably, some of the phenotypes determined by dendoU pan-neuronal silencing, i.e., pupal lethality, strongly reduced fly lifespan, juvenile phenotypes and severely impaired locomotion, overlap with those caused by dTDP-43 deregulation 17 . TDP-43 is an evolutionary conserved RNA/DNA binding protein, considered to be a neuronal activity-responsive factor and neurodegeneration hallmark 21, 22 . As shown in different model systems, TDP-43 cellular levels must be exquisitely regulated since even subtle alterations result in neurotoxicity 23, 24 . We demonstrate, through two independent RNAi lines, that dendoU knockdown causes an about 35% decrease of dTDP-43 protein, indicating that one relevant function of DendoU in Drosophila nervous system is to contribute to the control of dTDP-43 levels. These data suggest that DendoU-linked phenotypes are at least in part mediated by dTDP-43 loss-of-function. The involvement of other genes is expected in light of the more severe phenotype observed in dendoU RNAi flies compared to dTDP-43 RNAi . Moreover, since dTDP-43 mRNA is not a direct DendoU substrate, dTDP-43 regulation must be mediated by still unknown DendoU targets. Ongoing transcriptomics analysis aims at identifying DendoU target genes responsible for the regulation of i) dTDP-43 dependent circuit; ii) other molecular pathways underlying the observed dramatic phenotypes. Inside the nervous system, DendoU contribution is not restricted to individual neuronal sub-types but extended to complex neuronal networks, largely dependent on cholinergic neurons. Indeed, dendoU depletion in this neuronal subclass recapitulates the pan-neuronal phenotypes indicating a defect in excitatory inputs to CCAP/bursicon and motor neurons. This is in line with the already demonstrated defects in synaptic efficacy caused by deregulation of dTDP-43 20 .