Expression of mutant CHMP2B linked to neurodegeneration in humans disrupts circadian rhythms in Drosophila

Abstract

Mutations in CHMP2B, an ESCRT-III (endosomal sorting complexes required for transport) component, are associated with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Neurodegenerative disorders including FTD are also associated with a disruption in circadian rhythms, but the mechanism underlying this defect is not well understood. Here, we ectopically expressed the human CHMP2B variant associated with FTD (CHMP2B^Intron5) in flies using the GMR-GAL4 driver (GMR>CHMP2B^Intron5) and analyzed their circadian rhythms at behavioral, cellular, and biochemical level. In GMR>CHMP2B^Intron5 flies, we observed disrupted eclosion rhythms, shortened free-running circadian locomotor period, and reduced levels of timeless (tim) mRNA-a circadian pacemaker gene. We also observed that the GMR-GAL4 driver, primarily known for its expression in the retina, drives expression in a subset of tim expressing neurons in the optic lobe of the brain. The patterning of these GMR- and tim-positive neurons in the optic lobe, which appears distinct from the putative clusters of circadian pacemaker neurons in the fly brain, was disrupted in GMR>CHMP2B^Intron5 flies. These results demonstrate that CHMP2B^Intron5 can disrupt the normal function of the circadian clock in Drosophila.

Keywords: CHMP2B; ESCRT; circadian Rhythms; endosomal Lysosomal Pathway.