Roles of the RNA-Binding Protein TDP-43 in Sleep and Locomotor Activity in Drosophila

Abstract

Amyotrophic lateral sclerosis (ALS) is a lethal, progressive neurodegenerative disease that leads to death of motors neurons, loss of voluntary muscles, respiratory failure, progressive muscle paralysis and death within 3-5 years. In the recent past, the RNA binding protein TDP-43 has emerged as a major player in the pathology of this fatal disease due to its linkage to the majority of ALS cases known to date. This discovery has led to an avalanche of research investigating the role of TDP-43 in ALS. Here, we use the Drosophila Activity Monitoring (DAM) system to investigate sleep and locomotor behavior in adult flies expressing wild type or mutant variants of TDP-43 in motor neurons or glia. We show that activity is significantly decreased in all variants compared to the control, and that average total sleep is increased in wild-type TDP-43 flies but decreased in mutant flies. Furthermore mutant and wild-type flies exhibit an increased number of sleep bouts and a decreased length of sleep bout during the day and night compared to the control. These newly discovered sleep phenotypes in the Drosophila model resemble restlessness and sleeplessness reported in ALS patients and open up new avenues of study for the role of TDP-43 in motor neuron disease and neurodegeneration.