Circadian Clocks Function in Concert with Heat Shock Organizing Protein to Modulate Mutant Huntingtin Aggregation and Toxicity

Abstract

Summary: Neurodegenerative diseases commonly involve the disruption of circadian rhythms. Studies indicate that mutant Huntingtin (mHtt), the cause of Huntington’s disease (HD), disrupts circadian rhythms often before motor symptoms are evident. Yet little is known about the molecular mechanisms by which mHtt impairs circadian rhythmicity and whether circadian clocks can modulate HD pathogenesis. To address this question, we used a Drosophila HD model. We found that both environmental and genetic perturbations of the circadian clock alter mHtt-mediated neurodegeneration. To identify potential genetic pathways that mediate these effects, we applied a behavioral platform to screen for clock-regulated HD suppressors, identifying a role for Heat Shock Protein 70/90 Organizing Protein (Hop). Hop knockdown paradoxically reduces mHtt aggregation and toxicity. These studies demonstrate a role for the circadian clock in a neurodegenerative disease model and reveal a clock-regulated molecular and cellular pathway that links clock function to neurodegenerative disease. : Disruption of circadian rhythms is frequently observed across a range of neurodegenerative diseases. Here, Xu et al. demonstrate that perturbation of circadian clocks alters the toxicity of the mutant Huntingtin protein, the cause of Huntington’s disease (HD). Moreover, they reveal a key mechanistic link between the clock and HD. Keywords: circadian, Huntington’s disease, heat shock, transcriptome, genetic screen