TDP-43 impairs sleep in <i>Drosophila</i> through <i>Ataxin-2</i>-dependent metabolic disturbance.

Abstract

Neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal dementia are associated with substantial sleep disruption, which may accelerate cognitive decline and brain degeneration. Here, we define a role for trans-activation response element (TAR) DNA binding protein 43 (TDP-43), a protein associated with human neurodegenerative disease, in regulating sleep using <i>Drosophila</i>. Expression of TDP-43 severely disrupts sleep, and the sleep deficit is rescued by <i>Atx2</i> knockdown. Brain RNA sequencing revealed that <i>Atx2</i> RNA interference regulates transcripts enriched for small-molecule metabolic signaling in TDP-43 brains. Focusing on these <i>Atx2</i>-regulated genes, we identified suppressors of the TDP-43 sleep phenotype enriched for metabolism pathways. Knockdown of <i>Atx2</i> or treatment with rapamycin attenuated the sleep phenotype and mitigated the disruption of small-molecule glycogen metabolism caused by TDP-43. Our findings provide a connection between toxicity of TDP-43 and sleep disturbances and highlight key aspects of metabolism that interplay with TDP-43 toxicity upon <i>Atx2</i> rescue.