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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.
Bd. 114
(2017)
Heft 23
.
- S. E4676-E4685.
ISSN 1091-6490
DOI: https://doi.org/10.1073/pnas.1614943114
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 TNFalpha. Together, our results demonstrate a multifaceted protective potential of NRF2 signaling in key cell types relevant to HD pathology.
Weitere Angaben
| Publikationsform: | Artikel in einer Zeitschrift |
|---|---|
| Begutachteter Beitrag: | Ja |
| Institutionen der Universität: | Fakultäten Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Chemie Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Chemie > Lehrstuhl Biochemie Fakultäten > Fakultät für Biologie, Chemie und Geowissenschaften > Fachgruppe Chemie > Lehrstuhl Biochemie > Lehrstuhl Biochemie I - Proteinbiochemie der Signaltransduktion - Univ.-Prof. Dr. Clemens Steegborn |
| Titel an der UBT entstanden: | Nein |
| Themengebiete aus DDC: | 500 Naturwissenschaften und Mathematik 500 Naturwissenschaften und Mathematik > 540 Chemie 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften; Biologie |
| Eingestellt am: | 13 Feb 2018 08:09 |
| Letzte Änderung: | 05 Sep 2022 07:53 |
| URI: | https://eref.uni-bayreuth.de/id/eprint/42261 |