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

English version

Autoři: Fangke Xu ^aff001; Elzbieta Kula-Eversole ^aff001; Marta Iwanaszko ^aff002; Chunghun Lim ^aff001; Ravi Allada ^aff001
Působiště autorů: Department of Neurobiology, Northwestern University, Evanston, Illinois, United States of America ^aff001; Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America ^aff002
Vyšlo v časopise: Ataxin2 functions via CrebA to mediate Huntingtin toxicity in circadian clock neurons. PLoS Genet 15(10): e32767. doi:10.1371/journal.pgen.1008356
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008356

Souhrn

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.

Klíčová slova:

Circadian oscillators – Circadian rhythms – Huntington disease – Hyperexpression techniques – Neurons – RNA interference – Toxicity – cDNA libraries

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