Ataxin2 functions via CrebA to mediate Huntingtin toxicity in circadian clock neurons

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. Author summary Circadian clocks evolved to anticipate 24 h environmental rhythms driven by the earth's daily rotation and regulate nearly all aspects of behavior, physiology and the genome. Disruptions of the circadian clock have been associated with a wide range of human diseases, including neurodegenerative diseases such as Huntington's disease (HD). Using an HD animal model in which a mutant Huntingtin (mHtt) 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. Using transcriptomics, we identify the transcription factor CrebA as a potential target of both Atx2 and the circadian clock. Finally, we demonstrate a role for CrebA in mediating mHtt effects on circadian behavior, defining a novel Atx2-CrebA pathway in a neurodegenerative disease model. These studies define the molecular mechanisms by which mHtt can disrupt circadian rhythms identifying potential novel therapeutic targets for this uniformly fatal disease.