INSULIN SIGNALING AND PROTEIN SYNTHESIS DEFICITS IN MODELS OF TDP-43 PROTEINOPATHY

Abstract

Amyotrophic Lateral Sclerosis is a devastating disease that causes degeneration and death of motor neurons, leading to symptoms such as muscle weakness, speech impediment, difficulty swallowing, and paralysis. TDP-43 is a hallmark protein associated with ALS, with roles in RNA processing including protein synthesis. To determine this relationship, Drosophila overexpressing human wild-type TDP-43 (TDP-43WT) or mutant (TDP-43G298S) in neurons were tested for their ability to incorporate Puromycin, a tyrosyl-tRNA analog used to measure the rate of global translation. Western blotting experiments showed a significant reduction in global protein translation in Drosophila brain extracts in which TDP-43G298S was expressed panneuronally compared to w1118 controls. In addition, I used larval turning assays to conduct genetic interaction experiments between TDP-43 and insulin signaling components that ultimately modulate protein synthesis as well. These data suggest that TDP-43 may cause insulin resistance in motor neurons, contributing to the many-fold toxic qualities of this protein in ALS. Taken together, these experiments indicate that TDP-43G298S toxicity affects global translation in neurons and also causes insulin signaling deficits.