A large-scale RNAi screen in Drosophila unravels genetic modifiers of human TDP-43 toxicity

Edward Holostalo

Authors:  Edward HoLostalo, Deepak Chhangani, Lorena de Mena, Jessica Trochez, Nho Cao, Jada Lewis2, Pedro Fernandez-Funez, and Diego E. Rincon-Limas

Faculty Mentor:  Diego E. Rincon-Limas

College:  College of Medicine


Lou Gehrig’s disease currently affects 30,000 people in the US. TAR DNA-binding protein 43 (TDP-43) is associated with Lou Gehrig’s disease and front temporal dementia. There is a need to find effective treatments for these devastating disorders. A key challenge is identifying critical proteins and pathways that mediate TDP-43 insults. Drosophila models have reliable and easy-to-score phenotype in the eye. Using genetic modifiers expressing human TDP-43, crossing it with a next-generation library of 6,484 RNAi strains to assess the effect of silencing individual targets. Genes that suppressed the eye phenotype were catalogued as pathogenic factors, while those that enhanced were catalogued as potential neuroprotectors. We identified almost 300 modifiers of mutant TDP-43 toxicity in a primary screen. To date, there have been confirmed 100 robust suppressors, 80 enhancers and 20 lethals. In summary, this loss-of function genetic screen has led to the identification of several genes and molecular pathways not previously known to be associated with TDP-43 pathologies. The results will provide novel therapeutic targets to approach the devastating TDP-43 proteinopathies and will reveal which pathways could be targeted for better efficacy.

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