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

Luisa Quinti, Sharadha Dayalan Naidu, Ulrike Träge, Xiqun Chen, Kimberly Kegel-Gleason, David Lleres, Colúm Connolly, Vanita Chopra, Cho Low, Sebastien Moniot, Ellen Sapp, Adelaide R Tousley, Petr Vodicka, Michael J. Van Kanegan, Linda S. Kaltenbach, Lisa A Crawford, Matthew Fuszard, Maureen Higgins, James R.C. Miller, Ruth E. FarmerVijay Potluri, Susanta Samajdar, Lisa Meisel, Ningzhe Zhang, Andrew Snyder, Ross Stein, Steven M. Hersch, Lisa M. Ellerby, Eranthie Weerapana, Michael A. Schwarzschild, Clemens Steegborn, Blair R. Leavitt, Alexei Degterev, Sarah J. Tabrizi, Donald C. Lo, Marian DiFiglia, Leslie M. Thompson, Albena Dinkova-Kostova, Aleksey G. Kazantsev (Lead / Corresponding author)

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    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.

    Original languageEnglish
    Pages (from-to)e4676-e4685
    Number of pages10
    JournalProceedings of the National Academy of Sciences of the United States of America
    Issue number23
    Early online date22 May 2017
    Publication statusPublished - 6 Jun 2017


    • Huntington’s disease
    • KEAP1/NRF2/ARE
    • NRF2 inducer
    • Anti-Inflammatory Responses
    • Human Neural Stem Cells


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