Effect of USP14 inhibition on sleep disturbance in a Drosophila model of Parkinson's Disease

Sleep disturbances and circadian disruptions are associated with aging and neurodegenerative disorders. However, while alterations in 24-h circadian rhythms and sleep are common in older adults, they seem to be more severe in people that suffer age-related neurodegenerative disease. The mechanistic link between circadian rhythms and neurodegeneration is not fully understood, although proposed underlying pathways include alterations in protein homeostasis (proteostasis). Loss of proteostasis is well documented in neurodegenerative conditions, and seems to depend on the progressive pathological decline in the proteolytic activity of two major degradative systems: the ubiquitin-proteasome and the lysosome-autophagy system. Indeed, promoting proteasome or autophagy activity increases lifespan, and rescues the pathological phenotype of animal models of neurodegeneration, presumably by enhancing the degradation of misfolded proteins and dysfunctional organelles, which are known to accumulate in these models and to induce intracellular damage. While many studies investigate the effect of potentiating proteostasis to scavenge intracytoplasmic neurotoxic aggregates, very little attention has yet been paid to explore the potential link between alteration in protein homeostasis and (in)stability of core components of the circadian clock in neurodegenerative conditions. In this work we want to exploit drosophila models of Parkinson’s Disease (PD) to investigate the potential beneficial effect of enhancing proteostasis in the context of circadian and sleep disturbances. Our data show that inhibition of deubiquitinating enzyme USP14, which is known to enhance proteasome and autophagy activity, ameliorates sleep disturbances and circadian defects that are associated to two drosophila models of PD: the PINK1 and Parkin KO flies.