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

Title data

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.:
KEAP1-modifying small molecule reveals muted NRF2 signaling responses in neural stem cells from Huntington's disease patients.
In: Proceedings of the National Academy of Sciences of the United States of America. Vol. 114 (6 June 2017) Issue 23 . - E4676-E4685.
ISSN 1091-6490
DOI: https://doi.org/10.1073/pnas.1614943114

Abstract in another language

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 TNFalpha. Together, our results demonstrate a multifaceted protective potential of NRF2 signaling in key cell types relevant to HD pathology.

Further data

Item Type: Article in a journal
Refereed: Yes
Institutions of the University: Faculties
Faculties > Faculty of Biology, Chemistry and Earth Sciences
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biochemistry
Faculties > Faculty of Biology, Chemistry and Earth Sciences > Department of Chemistry > Chair Biochemistry > Chair Biochemistry - Univ.-Prof. Dr. Clemens Steegborn
Result of work at the UBT: No
DDC Subjects: 500 Science
500 Science > 540 Chemistry
500 Science > 570 Life sciences, biology
Date Deposited: 13 Feb 2018 08:09
Last Modified: 13 Feb 2018 08:09
URI: https://eref.uni-bayreuth.de/id/eprint/42261