Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 23, Pages E4676-E4685Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1614943114
Keywords
Huntington's disease; KEAP1/NRF2/ARE signaling; NRF2 inducer; antiinflammatory responses; human neural stem cells
Categories
Funding
- NIH [U01-NS066912, R01NS04528]
- National Institute of General Medical Sciences (NIGMS) [GM080356]
- Biotechnology and Biological Sciences Research Council [BB/J007498/1, BB/L01923X/1]
- Cancer Research UK [C20953/A18644]
- RJG Foundation
- CHDI Foundation
- Alzheimer Forschung Initiative [14834]
- NINDS [NS100529]
- BBSRC [BB/L01923X/1, BB/J007498/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/J007498/1, BB/L01923X/1] Funding Source: researchfish
- Cancer Research UK [18644] Funding Source: researchfish
- Medical Research Council [MR/P007015/1, 1354752] Funding Source: researchfish
- Rosetrees Trust [M574, M220] Funding Source: researchfish
- Wellcome Trust [200181/Z/15/Z] Funding Source: researchfish
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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 TNF alpha. Together, our results demonstrate a multifaceted protective potential of NRF2 signaling in key cell types relevant to HD pathology.
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