Circadian Clocks Function in Concert with Heat Shock Organizing Protein to Modulate Mutant Huntingtin Aggregation and Toxicity
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...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-04-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124719303225 |
| _version_ | 1811281701968543744 |
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| author | Fangke Xu Elzbieta Kula-Eversole Marta Iwanaszko Alan L. Hutchison Aaron Dinner Ravi Allada |
| author_facet | Fangke Xu Elzbieta Kula-Eversole Marta Iwanaszko Alan L. Hutchison Aaron Dinner Ravi Allada |
| author_sort | Fangke Xu |
| collection | DOAJ |
| description | 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 |
| first_indexed | 2024-04-13T01:38:20Z |
| format | Article |
| id | doaj.art-32158e3723d44796b12f4653fb0b32e2 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-13T01:38:20Z |
| publishDate | 2019-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-32158e3723d44796b12f4653fb0b32e22022-12-22T03:08:16ZengElsevierCell Reports2211-12472019-04-012715970.e4Circadian Clocks Function in Concert with Heat Shock Organizing Protein to Modulate Mutant Huntingtin Aggregation and ToxicityFangke Xu0Elzbieta Kula-Eversole1Marta Iwanaszko2Alan L. Hutchison3Aaron Dinner4Ravi Allada5Department of Neurobiology, Northwestern University, Evanston, IL, USADepartment of Neurobiology, Northwestern University, Evanston, IL, USAFeinberg School of Medicine, Northwestern University, Chicago, IL, USAMedical Scientist Training Program, University of Chicago, Chicago, IL, USAJames Franck Institute, University of Chicago, Chicago, IL, USADepartment of Neurobiology, Northwestern University, Evanston, IL, USA; Corresponding authorSummary: 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 screenhttp://www.sciencedirect.com/science/article/pii/S2211124719303225 |
| spellingShingle | Fangke Xu Elzbieta Kula-Eversole Marta Iwanaszko Alan L. Hutchison Aaron Dinner Ravi Allada Circadian Clocks Function in Concert with Heat Shock Organizing Protein to Modulate Mutant Huntingtin Aggregation and Toxicity Cell Reports |
| title | Circadian Clocks Function in Concert with Heat Shock Organizing Protein to Modulate Mutant Huntingtin Aggregation and Toxicity |
| title_full | Circadian Clocks Function in Concert with Heat Shock Organizing Protein to Modulate Mutant Huntingtin Aggregation and Toxicity |
| title_fullStr | Circadian Clocks Function in Concert with Heat Shock Organizing Protein to Modulate Mutant Huntingtin Aggregation and Toxicity |
| title_full_unstemmed | Circadian Clocks Function in Concert with Heat Shock Organizing Protein to Modulate Mutant Huntingtin Aggregation and Toxicity |
| title_short | Circadian Clocks Function in Concert with Heat Shock Organizing Protein to Modulate Mutant Huntingtin Aggregation and Toxicity |
| title_sort | circadian clocks function in concert with heat shock organizing protein to modulate mutant huntingtin aggregation and toxicity |
| url | http://www.sciencedirect.com/science/article/pii/S2211124719303225 |
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