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

Titelangaben

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 (6 Juni 2017) Heft 23 . - E4676-E4685.
ISSN 1091-6490
DOI: 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 - 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: 13 Feb 2018 08:09
URI: https://eref.uni-bayreuth.de/id/eprint/42261