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Proc Natl Acad Sci U S A. 2017 Jun 6;114(23):E4676-E4685. doi: 10.1073/pnas.1614943114. Epub 2017 May 22.

KEAP1-modifying small molecule reveals muted NRF2 signaling responses in neural stem cells from Huntington's disease patients.

Author information

1
Department of Neurology, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114.
2
Division of Cancer Research, School of Medicine, University of Dundee, Dundee DD1 9SY, Scotland, United Kingdom.
3
Department of Neurodegenerative Disease, Institute of Neurology, University College London, London WC1N 3BG, United Kingdom.
4
Institute of Molecular Genetics of Montpellier, F-34293 Montpellier, France.
5
Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V5Z 4H4.
6
Department of Developmental, Molecular and Chemical Biology, Tufts University, Boston, MA 02111.
7
Department of Biochemistry, University of Bayreuth, 95447 Bayreuth, Germany.
8
Center for Drug Discovery, Duke University Medical Center, Durham, NC 27710.
9
Department of Neurobiology, Duke University Medical Center, Durham, NC 27710.
10
Department of Chemistry, Boston College, Chestnut Hill, MA 02467.
11
Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom.
12
Department of Medicinal Chemistry, Aurigene Discovery Technologies Limited, Bangalore 560 100, India.
13
Buck Institute for Research on Aging, Novato, CA 94945.
14
Targanox, Cambridge Research Laboratories, Cambridge, MA 02139.
15
Department of Biological Chemistry, University of California, Irvine, CA 92697.
16
Department of Neurobiology and Behavior, University of California, Irvine, CA 92697.
17
Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697.
18
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
19
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
20
Department of Neurology, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114; akazantsev47@gmail.com.

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.

KEYWORDS:

Huntington’s disease; KEAP1/NRF2/ARE signaling; NRF2 inducer; antiinflammatory responses; human neural stem cells

PMID:
28533375
PMCID:
PMC5468652
DOI:
10.1073/pnas.1614943114
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

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