Age-dependent deterioration in motor functions, circadian rhythm and sleep in Drosophila model of Amyotrophic Lateral Sclerosis 8

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a fatal, motor neurodegenerative disease affecting thousands of people every year worldwide. ~50% of the ALS cases patients display behavioural changes, cognitive and executive dysfunction along with motor defects. In this study, I have used a Drosophila model of ALS to investigate the effects on behavioural patterns. The disease model is Drosophila variant with a point mutation in the VAP gene, where Proline in the 58th position is replaced by Serine (VAPP58S), achieved by CRISPR-Cas9 genome editing. Continuous monitoring of the daily activity of VAPP58S flies using the Drosophila Activity Monitoring (DAM) system revealed that the flies exhibit progressive age-dependent motor defects and have a reduced lifespan. In addition to this, I found that these flies also show changes in their circadian rhythms and also sleep cycles. Mutant animals become arrhythmic with increasing age and lose the periodicity in their day-to-day motor activity. They have disturbed, fragmented sleep with number of ‘short’ sleep bouts increasing with age. This deterioration in lifespan, motor functions, circadian rhythm, and sleep is rescued by introducing a single copy of VAPWT construct in the mutant flies. My results underscore the utility of modelling human neurodegenerative disease in fly models. Our laboratory can now use the diverse genetic toolkit available in Drosophila to probe for molecular relationships between neurodegenerative disease and behaviour.