TDP-43 expression impairs sleep in Drosophila and is rescued by Ataxin-2 knockdown

Exploring the intricate link between sleep and brain degeneration holds great promise for the development of effective therapeutics. Here we provide novel insights into the role of TDP-43 and Atx2 in regulating sleep and neurodegeneration using Drosophila. We demonstrate that expression of TDP-43 severely disrupts sleep, resulting in reduced sleep duration of the affected animals. Sleep disruption by TDP-43 is completely rescued by Atx2 knockdown. To unravel the underlying mechanism of TDP43 sleep disruption and Atx2-mediated rescue, we conducted brain RNA sequencing analysis from flies expressing TDP-43 with or without Atx2 knockdown. Among RNAseq changes, we observed upregulation of genes associated with small molecule metabolism with TDP-43 expression, followed by their subsequent downregulation upon Atx2 knockdown. Utilizing these Atx2-regulated genes, we conducted an RNAi screen to identify additional sleep modifiers that interact with TDP-43. Drosophila brain tissue RNA-sequencing used to investigate the underlying mechanism of TDP43 sleep disruption and Atx2-mediated rescue