Authors: Quinlan Mewborne; Jessica Chalk ; Junli Gao; Ke Zhang
Affiliation: Mayo Clinic Jacksonville
Keywords: a. neural degeneration; h. other (Stress Granule Formation )
Amyotrophic lateral sclerosis (ALS) is a degenerative disease of the motor neurons sometimes associated with frontotemporal dementia (FTD). These two neurodegenerative diseases are progressive, increasingly prevalent, and currently incurable. A major challenge of the therapeutic development of these diseases is our incomplete understanding of the pathogenic mechanism. Previous studies have suggested that stress granules (SGs), RNA/protein condensates assembled in cells under stress, play a critical role in ALS/FTD pathogenesis. Consistent with this notion, chemical inhibitors suppressing SG assembly suppress neurodegeneration in cellular and animal models of ALS/FTD. However, these inhibitors exhibit detrimental side effects in mammals in preclinical studies, preventing their translation into clinics. Thus, we propose to use a fly model to identify novel ways targeting SG assembly as potential therapeutic strategies for ALS/FTD.
Tar DNA-binding protein 43 (TDP-43) is an SG protein, whose cytoplasmic aggregation has been implicated in ~98% of ALS and ~45% of FTD. Indeed, SG assembly has been shown to trigger TDP-43 aggregation in multiple models of ALS/FTD. Consistent with these data, overexpressing a cytoplasmic form of TDP-43 causes eye degeneration in flies. Using this model, we screened through the RNAi of 250 fly genes whose human homolog have been shown to promote SG assembly in cultured cells. We identified ~20 genes whose RNAi strongly or moderately suppresses TDP-43-mediated eye degeneration in our flies and will further characterize their roles in ALS/FTD pathogenesis.