J. Paul Taylor, MD, PhD
Altered RNA Metabolism in C9ORF72-associated ALS
We generated and characterized a fruit fly model of C9ORF72-associated hexanucleotide repeat expansion. This model shows degeneration dependent on the number of GGGGCC-repeats, accumulation of expanded GGGGCC RNA and RAN translation, essentially providing a genetically tractable model of C9ALS/FTD. We used this fly model to conduct an unbiased genetic screen that identified multiple RNA-binding proteins that regulate aspects of pre-mRNA splicing as strong genetic modifiers of this hexanucleotide repeat toxicity. This discovery strongly implies that accrual of GGGGCC RNA impairs key aspects of RNA metabolism. In this project we will test the hypothesis that certain specific aspects of pre-mRNA processing are impaired in C9ORF72-associated ALS.