title: TDP-43 loss-of-function causes neuronal loss due to defective steroid receptor-mediated gene program switching in Drosophila.
abstract: TDP-43 proteinopathy is strongly implicated in the pathogenesis of amyotrophic lateral sclerosis and related neurodegenerative disorders. Whether TDP-43 neurotoxicity is caused by a novel toxic gain-of-function mechanism of the aggregates or by a loss of its normal function is unknown. We increased and decreased expression of TDP-43 (dTDP-43) in Drosophila. Although upregulation of dTDP-43 induced neuronal ubiquitin and dTDP-43-positive inclusions, both up- and downregulated dTDP-43 resulted in selective apoptosis of bursicon neurons and highly similar transcriptome alterations at the pupal-adult transition. Gene network analysis and genetic validation showed that both up- and downregulated dTDP-43 directly and dramatically increased the expression of the neuronal microtubule-associated protein Map205, resulting in cytoplasmic accumulations of the ecdysteroid receptor (EcR) and a failure to switch EcR-dependent gene programs from a pupal to adult pattern. We propose that dTDP-43 neurotoxicity is caused by a loss of its normal function.
authors: Laboratory of Behavioral and Developmental Genetics, Center of Human Genetics, University of Leuven, B3000 Leuven, Belgium.
authors: Lies
authors: L
authors: Vanden Broeck
authors: Marina
authors: M
authors: Naval-Sánchez
authors: Yoshitsugu
authors: Y
authors: Adachi
authors: Danielle
authors: D
authors: Diaper
authors: Pierre
authors: P
authors: Dourlen
authors: Julien
authors: J
authors: Chapuis
authors: Gernot
authors: G
authors: Kleinberger
authors: Marc
authors: M
authors: Gistelinck
authors: Christine
authors: C
authors: Van Broeckhoven
authors: Jean-Charles
authors: JC
authors: Lambert
authors: Frank
authors: F
authors: Hirth
authors: Stein
authors: S
authors: Aerts
authors: Patrick
authors: P
authors: Callaerts
authors: Bart
authors: B
authors: Dermaut
mesh_terms: D000375:Aging / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D019070:Cell Lineage / Q000235:genetics; D048430:Cell Shape; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology* / Q000235:genetics* / Q000254:growth & development; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks / Q000235:genetics; D005812:Genes, Switch; D005838:Genotype; D006801:Humans; D007447:Invertebrate Hormones / Q000378:metabolism; D008675:Metamorphosis, Biological / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism*; D059467:Transcriptome / Q000235:genetics; D014921:Wings, Animal / Q000166:cytology / Q000254:growth & development
chemical_list: D004268:DNA-Binding Proteins; D007447:Invertebrate Hormones; D012333:RNA, Messenger; D011987:Receptors, Steroid; C055469:ecdysone receptor; C002295:bursicon