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

Fangke Xu, Elzbieta Kula-Eversole, Marta Iwanaszko, Alan L. Hutchison, Aaron Dinner, Ravi Allada*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)59-70.e4
JournalCell reports
Volume27
Issue number1
DOIs
StatePublished - Apr 2 2019

Keywords

  • Huntington's disease
  • circadian
  • genetic screen
  • heat shock
  • transcriptome

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint

Dive into the research topics of 'Circadian Clocks Function in Concert with Heat Shock Organizing Protein to Modulate Mutant Huntingtin Aggregation and Toxicity'. Together they form a unique fingerprint.

Cite this