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 of motor neurons. The discovery of mutations in the gene encoding an RNA-binding protein, TAR DNA-binding protein of 43 kD (TDP-43), in familial ALS, strongly implicated abnormalities in RNA 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.