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

• Published in: PLoS genetics Vol. 15; no. 10; p. e1008356
• Main Authors: Xu, Fangke, Kula-Eversole, Elzbieta, Iwanaszko, Marta, Lim, Chunghun, Allada, Ravi
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 08-10-2019; Public Library of Science (PLoS)
• Subjects: Amyotrophic lateral sclerosis; Animal behavior; Animal models; Animals; Ataxin-2 - genetics; Biology and life sciences; Brain; Circadian Clocks - genetics; Circadian rhythm; Circadian Rhythm - genetics; Circadian rhythms; Cyclic adenosine monophosphate; Cyclic AMP Response Element-Binding Protein A - genetics; Disease Models, Animal; Diurnal; Drosophila; Drosophila melanogaster - genetics; Drosophila Proteins - genetics; Fragile X Mental Retardation Protein - genetics; Fragile X syndrome; Genetic engineering; Genetic screening; Genetic testing; High definition television; Humans; Huntingtin; Huntingtin Protein - genetics; Huntington Disease - genetics; Huntington Disease - pathology; Huntington's disease; Hypothalamus; Intellectual disabilities; Medicine and Health Sciences; Mental disorders; Mutant Proteins - genetics; Neostriatum; Nervous system diseases; Neurodegeneration; Neurodegenerative diseases; Neurons; Neurons - metabolism; Novels; Pathogenicity; Protein binding; Research and Analysis Methods; RNA interference; RNA-mediated interference; Signal Transduction - genetics; Toxicity; Transcription; Grand Rapids Michigan; Chicago Illinois; United States > US; Illinois; Michigan
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1008356

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.