@article{0795dcd427ff43f7a2ff0fa12264571a,
title = "Circadian Clocks Function in Concert with Heat Shock Organizing Protein to Modulate Mutant Huntingtin Aggregation and Toxicity",
abstract = "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 = "Huntington's disease, circadian, genetic screen, heat shock, transcriptome",
author = "Fangke Xu and Elzbieta Kula-Eversole and Marta Iwanaszko and Hutchison, {Alan L.} and Aaron Dinner and Ravi Allada",
note = "Funding Information: We thank R. Morimoto, G. Beitel, and R. Cowell for helpful comments and advice. We thank J. Littleton, N. Perrimon, J. Wu, and the Bloomington Stock Center for fly strains. We thank M. Rosbash and M. Nitabach for antibodies. The research was supported by DARPA ( D12AP00023 ) and the Brain Research Foundation . The content of the information does not necessarily reflect the position or the policy of the government, and no official endorsement should be inferred. F.X. was supported by a Northwestern University graduate fellowship in association with NIH T32HL007909 . Funding Information: We thank R. Morimoto, G. Beitel, and R. Cowell for helpful comments and advice. We thank J. Littleton, N. Perrimon, J. Wu, and the Bloomington Stock Center for fly strains. We thank M. Rosbash and M. Nitabach for antibodies. The research was supported by DARPA (D12AP00023) and the Brain Research Foundation. The content of the information does not necessarily reflect the position or the policy of the government, and no official endorsement should be inferred. F.X. was supported by a Northwestern University graduate fellowship in association with NIH T32HL007909. F.X. E.K.-E. and R.A. conceived the experiments; F.X. and E.K.-E. performed all experiments; F.X. E.K.-E. M.I. A.L.H. A.D. and R.A. analyzed the data; and F.X. and R.A. wrote the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 The Author(s)",
year = "2019",
month = apr,
day = "2",
doi = "10.1016/j.celrep.2019.03.015",
language = "English (US)",
volume = "27",
pages = "59--70.e4",
journal = "Cell reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "1",
}