Abstract
Disrupted circadian rhythms is a prominent and early feature of neurodegenerative diseases including Huntington’s disease (HD). In HD patients and animal models, striatal and hypothalamic neurons expressing molecular circadian clocks are targets of mutant Huntingtin (mHtt) pathogenicity. Yet how mHtt disrupts circadian rhythms remains unclear. In a genetic screen for modifiers of mHtt effects on circadian behavior in Drosophila, we discovered a role for the neurodegenerative disease gene Ataxin2 (Atx2). Genetic manipulations of Atx2 modify the impact of mHtt on circadian behavior as well as mHtt aggregation and demonstrate a role for Atx2 in promoting mHtt aggregation as well as mHtt-mediated neuronal dysfunction. RNAi knockdown of the Fragile X mental retardation gene, dfmr1, an Atx2 partner, also partially suppresses mHtt effects and Atx2 effects depend on dfmr1. Atx2 knockdown reduces the cAMP response binding protein A (CrebA) transcript at dawn. CrebA transcript level shows a prominent diurnal regulation in clock neurons. Loss of CrebA also partially suppresses mHtt effects on behavior and cell loss and restoration of CrebA can suppress Atx2 effects. Our results indicate a prominent role of Atx2 in mediating mHtt pathology, specifically via its regulation of CrebA, defining a novel molecular pathway in HD pathogenesis.
Highlights
Circadian disruption is prevalent in Huntington’s disease (HD) patients and animal models
Using an HD animal model in which a mutant Huntingtin protein is expressed, we identify a role for the RNA binding protein and neurodegenerative disease gene Ataxin-2 (Atx2) in mediating mHtt effects on circadian behavioral rhythms
To discover genes important for mHtt effects on circadian rhythms, we performed an RNAi screen to look for modifier effects of mHtt induced arrhythmicity by expressing HttQ128 in Pigment Dispersing Factor (PDF)+ LNv using PdfGAL4 (PdfGAL4/UAS-HttQ128) [43, 55, 56] (S1 Fig)
Summary
Circadian disruption is prevalent in Huntington’s disease (HD) patients and animal models. Circadian behavioral rhythms are strongly disrupted in HD patients [3,4,5] and in animal models [5,6,7,8]. In postmortem HD brains, the numbers of master circadian pacemaker neurons in the hypothalamic suprachiasmatic nucleus (SCN) are reduced, especially of the subset expressing the neuropeptide vasoactive intestinal peptide (VIP) [16]. In flies, mHtt expression selectively reduces the number of a subset of clock neurons, the small ventral lateral neurons (sLNv), important for free running circadian behavior [7]. The core circadian oscillator is evident outside of the SCN, including in the striatum, and striatal molecular oscillations are altered suggesting that there are common mHtt mechanisms between the SCN and striatum
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
