TDP-43 Loss-of-Function Causes Neuronal Loss Due to Defective Steroid Receptor-Mediated Gene Program Switching in Drosophila

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. [Display omitted] ► Gain or loss of dTDP-43 causes degeneration of neurons responsible for adult eclosion ► Gain or loss of dTDP-43 directly deregulates Map205 expression ► Map205-overexpression-defective EcR-dependent gene network switching ► dTDP-43-mediated neurodegeneration is caused by a loss of its normal function TDP-43 is a DNA/RNA binding protein implicated in amyotrophic lateral sclerosis and frontotemporal dementia. Callaerts, Dermaut, and colleagues describe a neuronal function for TDP-43 in Drosophila, showing that both increased and decreased TDP-43 levels cause selective and specific loss of neuroendocrine bursicon neurons at the pupal-to-adult transition. Using deep RNA sequencing, they show that this neurotoxicity correlates with a disruption of ecdysteroid receptor-mediated gene program switching. Their results support a loss-of-function mechanism in TDP-43-mediated neurotoxicity.