Voigt, AaronAaronVoigtHerholz, DavidDavidHerholzFiesel, Fabienne C.Fabienne C.FieselKaur, KavitaKavitaKaurMüller, DanielDanielMüllerKarsten, PeterPeterKarstenWeber, Stephanie S.Stephanie S.WeberKahle, Philipp J.Philipp J.KahleMarquardt, TillTillMarquardtSchulz, JörgJörgSchulz2019-07-092019-07-092010https://resolver.sub.uni-goettingen.de/purl?gro-2/60347Alteration and/or mutations of the ribonucleoprotein TDP-43 have been firmly linked to human neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). The relative impacts of TDP-43 alteration, mutation, or inherent protein function on neural integrity, however, remain less clear--a situation confounded by conflicting reports based on transient and/or random-insertion transgenic expression. We therefore performed a stringent comparative investigation of impacts of these TDP-43 modifications on neural integrity in vivo. To achieve this, we systematically screened ALS/FTLD-associated and synthetic TDP-43 isoforms via same-site gene insertion and neural expression in Drosophila; followed by transposon-based motor neuron-specific transgenesis in a chick vertebrate system. Using this bi-systemic approach we uncovered a requirement of inherent TDP-43 RNA-binding function--but not ALS/FTLD-linked mutation, mislocalization, or truncation--for TDP-43-mediated neurotoxicity in vivo.enCC BY 2.5https://creativecommons.org/licenses/by/2.5610Amyotrophic Lateral SclerosisAnimalsCell LineChickensDNA-Binding ProteinsDrosophila melanogasterFrontotemporal Lobar DegenerationGene Expression RegulationHumansIntracellular SpaceLocomotionLongevityMaleMotor NeuronsMutationNeuronsOrgan SpecificityProtein BindingProtein TransportRNAjournal_article10.1371/journal.pone.001224720806063573853https://resolver.sub.uni-goettingen.de/purl?gs-1/6913