RNA binding mediates neurotoxicity in the transgenic Drosophila model of TDP-43 proteinopathy

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive and selective loss ofmotor neurons.Thediscovery of mutations in thegeneencodinganRNA-bindingprotein,TARDNA-binding protein of 43 kD (TDP-43), in familial ALS, strongly implicated abnormalities inRNA processing in the pathogenesis of ALS, although the mechanisms whereby TDP-43 leads to neurodegeneration remain elusive. To clarify the mechanism of degeneration caused by TDP-43, we generated transgenic Drosophila melanogaster expressing a series of systematically modified human TDP-43 genes in the retinal photoreceptor neurons. Overexpression of wild-type TDP-43 resultedinvacuolar degeneration of the photoreceptor neurons associated with thinning of the retina, which was significantly exacerbated bymutations of TDP-43 linked to familial ALS or disrupting its nuclear localization signal (NLS). Remarkably, these degenerative phenotypes were completely normalized by addition of a mutation or deletion of the RNA recognition motif that abolishes the RNA binding ability of TDP-43. Altogether, our results suggest that RNA binding is key to the neurodegeneration caused by overexpression of TDP-43, and that abnormalities in RNA processing may be crucial to the pathogenesis of TDP-43 proteinopathy.