title: Drosophila CG3303 is an essential endoribonuclease linked to TDP-43-mediated neurodegeneration.
abstract: Endoribonucleases participate in almost every step of eukaryotic RNA metabolism, acting either as degradative or biosynthetic enzymes. We previously identified the founding member of the Eukaryotic EndoU ribonuclease family, whose components display unique biochemical features and are flexibly involved in important biological processes, such as ribosome biogenesis, tumorigenesis and viral replication. Here we report the discovery of the CG3303 gene product, which we named DendoU, as a novel family member in Drosophila. Functional characterisation revealed that DendoU is essential for Drosophila viability and nervous system activity. Pan-neuronal silencing of dendoU resulted in fly immature phenotypes, highly reduced lifespan and dramatic motor performance defects. Neuron-subtype selective silencing showed that DendoU is particularly important in cholinergic circuits. At the molecular level, we unveiled that DendoU is a positive regulator of the neurodegeneration-associated protein dTDP-43, whose downregulation recapitulates the ensemble of dendoU-dependent phenotypes. This interdisciplinary work, which comprehends in silico, in vitro and in vivo studies, unveils a relevant role for DendoU in Drosophila nervous system physio-pathology and highlights that DendoU-mediated neurotoxicity is, at least in part, contributed by dTDP-43 loss-of-function.
authors.affiliation: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Laneve
authors.affiliation: Department of Biology and Biotechnology, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.|Institute Pasteur Fondazione Cenci-Bolognetti, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Piacentini
authors.affiliation: Department of Biology and Biotechnology, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.|Institute Pasteur Fondazione Cenci-Bolognetti, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: Assunta Maria
authors.initials: AM
authors.lastname: Casale
authors.affiliation: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy.|Department of Biology and Biotechnology, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Capauto
authors.affiliation: Department of Biology and Biotechnology, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: Ubaldo
authors.initials: U
authors.lastname: Gioia
authors.affiliation: Department of Biology and Biotechnology, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: Cappucci
authors.affiliation: Department of Biology and Biotechnology, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Di Carlo
authors.affiliation: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy.|Department of Biology and Biotechnology, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.|Institute Pasteur Fondazione Cenci-Bolognetti, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.|Institute of Molecular Biology and Pathology, National Research Council, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Bozzoni
authors.affiliation: Department of Biochemical Sciences, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: Patrizio
authors.initials: P
authors.lastname: Di Micco
authors.affiliation: Institute of Molecular Biology and Pathology, National Research Council, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Morea
authors.affiliation: Department of Biology and Biotechnology, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: Carmela Antonia
authors.initials: CA
authors.lastname: Di Franco
authors.affiliation: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy.|Institute of Molecular Biology and Pathology, National Research Council, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Caffarelli
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004330:Drosophila / Q000235:genetics* / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004722:Endoribonucleases / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D020868:Gene Silencing; D000073658:Loss of Function Mutation; D009043:Motor Activity; D019636:Neurodegenerative Diseases / Q000209:etiology* / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D017422:Sequence Analysis, DNA
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C000589036:TBPH protein, Drosophila; D004722:Endoribonucleases