TDP-43 neurotoxicity due to loss-of-function in Map205-dependent steroid receptor-mediated gene program switching in Drosophila. Bart Dermaut^1,2, Lies Vanden Broeck², Marina Naval Sanchez³, Yoshitsugu Adachi⁴, Danielle Diaper⁴, Pierre Dourlen¹, Julien Chapuis¹, Gernot Kleinberger⁵, Marc Gistelinck², Christine Van Broeckhoven⁵, Jean-Charles Lambert¹, Frank Hirth⁴, Stein Aerts³, Patrick Callaerts². 1) Inserm U744, Institut Pasteur de Lille, University of Lille 2, Lille, France; 2) Laboratory of Behavioral and Developmental Genetics, VIB Center for the Biology of Disease, University of Leuven, Belgium; 3) Laboratory of Computational Biology, Center of Human Genetics, University of Leuven, Belgium; 4) MRC Centre for Neurodegeneration Research, King's College London, Department of Neuroscience, Institute of Psychiatry, London, UK; 5) Department of Molecular Genetics, Neurodegenerative Brain Diseases Group, VIB, Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium.

   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 of the aggregates or by a loss of its normal function is unknown. We increased and decreased expression of TDP-43 (dTDP-43) in the Drosophila central nervous system and identified an important role for dTDP-43 in the survival of CCAP/bursicon neurons at the pupal-adult transition. While upregulation of dTDP-43 induced neuronal ubiquitin- and dTDP-43-positive inclusions, both up- and downregulated dTDP-43 resulted in neuronal apoptosis and highly similar transcriptome alterations in late metamorphosis. 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 in EcR-dependent gene program switching.