Cited by 140Genomics, phytochemicals, and oxidative stressGenetic Neurodegenerative DiseasesNuclear Receptors and Signaling

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

Open access
Quinti, Luisa, Dayalan Naidu, Sharadha, Träger, Ulrike, Chen, Xiqun, Kegel-Gleason, Kimberly, Llères, David, Connolly, Colúm, Chopra, Vanita +31 more·2017·Proceedings of the National Academy of Sciences

Abstract

Significance: Chronic neuroinflammation and oxidative stress are likely complicit in driving disease progression in Huntington's disease (HD). Here, we describe the mechanism of action of a unique chemical scaffold that is highly selective for activation of NRF2, the master transcriptional regulator of cellular antiinflammatory and antioxidant defense genes. The use of this scaffold revealed that NRF2 activation responses were muted in HD patient-derived neural stem cells, suggesting increased susceptibility of this critical renewable cell population to oxidative stress in HD brain. However, pharmacological activation of NRF2 was able to repress inflammatory responses in mouse microglia and astrocytes, the principal cellular mediators of neuroinflammation, and in blood monocytes from HD patients. Our results suggest multiple protective benefits of NRF2 activation for HD patients.

Integrity signals

Registry

Crossref · 10.1073/pnas.1614943114

Cites

101 of 101 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

The text we found for this paper looks like another document, so its claims and self-check weren’t run. The registry and citation checks still apply.

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The text we found for this paper looks like another document, so the self-check wasn’t run.

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Authors
Quinti, L., Dayalan Naidu, S., Träger, U., Chen, X., Kegel-Gleason, K., Llères, D., Connolly, C., Chopra, V., Low, C., Moniot, S., Sapp, E., Tousley, A. R., Vodicka, P., Van Kanegan, M. J., Kaltenbach, L. S., Crawford, L. A., Fuszard, M., Higgins, M., Miller, J. R. C., Farmer, R. E., Potluri, V., Samajdar, S., Meisel, L., Zhang, N., Snyder, A., Stein, R., Hersch, S. M., Ellerby, L. M., Weerapana, E., Schwarzschild, M. A., Steegborn, C., Leavitt, B. R., Degterev, A., Tabrizi, S. J., Lo, D. C., DiFiglia, M., Thompson, L. M., Dinkova-Kostova, A. T., & Kazantsev, A. G.
Affiliations
  • Harvard University (US)
  • Division of Cancer Research, School of Medicine, University of Dundee, Dundee DD1 9SY, Scotland, United Kingdom;
  • UCL Queen Square Institute of Neurology (GB)
  • Institut de Génétique Moléculaire de Montpellier (FR)
  • University of British Columbia (CA)
  • Tufts University (US)
  • University of Bayreuth (DE)
  • Department of Neurology, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114;
  • Center for Drug Discovery, Duke University Medical Center, Durham, NC 27710;
  • Duke Medical Center (US)
  • Boston College (US)
  • University of Dundee (GB)
  • London School of Hygiene & Tropical Medicine (GB)
  • Aurigene Discovery Technologies (India) (IN)
  • Buck Institute for Research on Aging (US)
  • Targanox, Cambridge Research Laboratories, Cambridge, MA 02139;
  • University of California, Irvine (US)
Venue
Proceedings of the National Academy of Sciences
Published
2017-05-22
Volume
114
Issue
23
Pages
E4676-E4685
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W2618292058
Cited by
140
References
101
Citations by year
2026: 9 · 2025: 14 · 2024: 16 · 2023: 18 · 2022: 25 · 2021: 13 · 2020: 24 · 2019: 9 · 2018: 7 · 2017: 5
FWCI
5.00
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Discovery Research Portal (University of Dundee) (publishedVersion, other-oa)
  • LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • ERef Bayreuth (University of Bayreuth) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • CHDI Foundation
  • Alzheimer Forschung Initiative (14834)
  • Wellcome Trust (200181/Z/15/Z)
  • Cancer Research UK (C20953 / A18644, A18644, BB/J007498/1, C20953, 18644)
  • Rosetrees Trust
  • National Institutes of Health
  • Directorate for Biological Sciences
  • Medical Research Council (MR/L02053X/1)
  • Biotechnology and Biological Sciences Research Council (BB/L01923X/1, BB/J007498/1)
  • National Institute of General Medical Sciences (GM080356, R01GM118431, R01GM080356)
  • National Institute of Neurological Disorders and Stroke (U01NS066912, NS100529, R01NS100529)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
Keywords
Keap1, Nrf2 signaling, Huntington's disease, small molecule inducers, E3 ubiquitin ligase, neural stem cells, microglia, astrocytes, monocytes, inflammatory cytokines, interleukin-6, neuroinflammation, antioxidant response
MeSH terms
Kelch-Like ECH-Associated Protein 1, Adult, Aged, Animals, Brain, Cells, Cultured, Disease Models, Animal, Female, Humans, Huntington Disease, Macrophages, Male, Mice, Inbred C57BL, Middle Aged, Protein Conformation, Signal Transduction, Cytokines, Microglia, Neuroprotective Agents, MPTP Poisoning, NF-E2-Related Factor 2, Mice, Rats, HEK293 Cells, Neural Stem Cells

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review