Quinti, L;
Naidu, SD;
Trager, U;
Chen, X;
Kegel-Gleason, K;
Lleres, D;
Connolly, C;
... Kazantsev, AG; + view all
(2017)
KEAP1-modifying small molecule reveals muted NRF2 signaling responses in neural stem cells from Huntington's disease patients.
PNAS - Proceedings of the National Academy of Sciences of the United States of America
, 114
(23)
E4676-E4685.
10.1073/pnas.1614943114.
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | KEAP1-modifying small molecule reveals muted NRF2 signaling responses in neural stem cells from Huntington's disease patients |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1073/pnas.1614943114 |
| Publisher version: | http://doi.org/10.1073/pnas.1614943114 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, Huntington's disease, KEAP1/NRF2/ARE signaling, NRF2 inducer, antiinflammatory responses, human neural stem cells, TRANSCRIPTION FACTOR NRF2, CUL3-BASED E3 LIGASE, FUMARIC-ACID ESTERS, OXIDATIVE STRESS, PARKINSONS-DISEASE, NEURODEGENERATIVE DISEASES, MOUSE MODEL, PROTEASOMAL DEGRADATION, MICROGLIAL ACTIVATION, KEAP1-NRF2 SYSTEM |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1554738 |
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