Forkhead Transcription Factor FOXO3a Levels are Increased in Huntington Disease Due to Overactivated Positive Autofeedback Loop [Neurobiology]

September 30th, 2014 by Kannike, K., Sepp, M., Zuccato, C., Cattaneo, E., Timmusk, T.

Huntington disease (HD) is a fatal autosomal dominant neurodegenerative disorder caused by increased number of CAG repeats in the HTT gene coding for huntingtin. Decreased neurotrophic support and increased mitochondrial and excitotoxic stress have been reported in HD striatal and cortical neurons. The members of class O forkhead (FOXO) transcription factor family, including FOXO3a, act as sensor proteins that are activated upon decreased survival signals and/or increased cellular stress. Using immunocytochemical screening in mouse striatal Hdh7/7 (wild-type), Hdh7/109 (heterozygous for HD mutation) and Hdh109/109 (homozygous for HD mutation) cells we identified FOXO3a as a differentially regulated transcription factor in HD. We report increased nuclear FOXO3a levels in mutant Hdh cells. Additionally, we show that treatment with mitochondrial toxin 3-nitropropionic acid (3-NP) results in enhanced nuclear localization of FOXO3a in wild-type Hdh7/7 cells and in rat primary cortical neurons. Furthermore, mRNA levels of Foxo3a are increased in mutant Hdh cells compared to wild-type cells and in 3-NP treated primary neurons compared to non-treated neurons. Similar increase was observed in the cortex of R6/2 mice and HD patients post mortem caudate tissue compared to controls. Using chromatin immunoprecipitation and reporter assays we demonstrate that FOXO3a regulates its own transcription by binding to the conserved response element in Foxo3a promoter. Altogether, the findings of this study suggest that FOXO3a levels are increased in HD cells as a result of overactive positive feedback loop.
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