Proceedings of the National Academy of Sciences of the United States of America · 2017
KEAP1-modifying small molecule reveals muted NRF2 signaling responses in neural stem cells from Huntington's disease patients.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Quinti Luisa, Dayalan Naidu Sharadha, Träger Ulrike, Chen Xiqun, Kegel-Gleason Kimberly, Llères David, Connolly Colúm, Chopra Vanita, Low Cho, Moniot Sébastien, Sapp Ellen, Tousley Adelaide R, Vodicka Petr, Van Kanegan Michael J, Kaltenbach Linda S, Crawford Lisa A, Fuszard Matthew, Higgins Maureen, Miller James R C, Farmer Ruth E, Potluri Vijay, Samajdar Susanta, Meisel Lisa, Zhang Ningzhe, Snyder Andrew, Stein Ross, Hersch Steven M, Ellerby Lisa M, Weerapana Eranthie, Schwarzschild Michael A, Steegborn Clemens, Leavitt Blair R, Degterev Alexei, Tabrizi Sarah J, Lo Donald C, DiFiglia Marian, Thompson Leslie M, Dinkova-Kostova Albena T, Kazantsev Aleksey G
Аннотация
The activity of the transcription factor nuclear factor-erythroid 2 p45-derived factor 2 (NRF2) is orchestrated and amplified through enhanced transcription of antioxidant and antiinflammatory target genes. The present study has characterized a triazole-containing inducer of NRF2 and elucidated the mechanism by which this molecule activates NRF2 signaling. In a highly selective manner, the compound covalently modifies a critical stress-sensor cysteine (C151) of the E3 ligase substrate adaptor protein Kelch-like ECH-associated protein 1 (KEAP1), the primary negative regulator of NRF2. We further used this inducer to probe the functional consequences of selective activation of NRF2 signaling in Huntington's disease (HD) mouse and human model systems. Surprisingly, we discovered a muted NRF2 activation response in human HD neural stem cells, which was restored by genetic correction of the disease-causing mutation. In contrast, selective activation of NRF2 signaling potently repressed the release of the proinflammatory cytokine IL-6 in primary mouse HD and WT microglia and astrocytes. Moreover, in primary monocytes from HD patients and healthy subjects, NRF2 induction repressed expression of the proinflammatory cytokines IL-1, IL-6, IL-8, and TNFα. Together, our results demonstrate a multifaceted protective potential of NRF2 signaling in key cell types relevant to HD pathology.