A gain of toxic function hypothesis via accumulated RNA-binding protein and repeat RNA in the pathogenesis of ALS and its validation in vivo

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Based on the hypothesis that abnormal accumulation of RNA would trigger aggregation and accumulation of the RNA-binding proteins, eventually leading to neurodegeneration in the pathogenesis of amyotrophic lateral sclerosis (ALS), 1) we established novel ALS model flies expressing expanded GGGGCC repeat RNA, which mimic neurological phenotypes and pathology of human ALS patients. 2) Furthermore, using this newly-established ALS models flies, we have successfully identified some RNA-binding proteins that can modify the toxicity of expanded GGGGCC repeat RNA in vivo. We therefore conclude that RNA-binding proteins are involved in neurotoxicity of abnormal RNA accumulation, which can contribute to the pathomechanism of ALS.