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

Published

Journal Article

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.

Full Text

Cited 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, AR; Vodicka, P; Van Kanegan, MJ; Kaltenbach, LS; Crawford, LA; Fuszard, M; Higgins, M; Miller, JRC; Farmer, RE; Potluri, V; Samajdar, S; Meisel, L; Zhang, N; Snyder, A; Stein, R; Hersch, SM; Ellerby, LM; Weerapana, E; Schwarzschild, MA; Steegborn, C; Leavitt, BR; Degterev, A; Tabrizi, SJ; Lo, DC; DiFiglia, M; Thompson, LM; Dinkova-Kostova, AT; Kazantsev, AG

Published Date

  • June 2017

Published In

Volume / Issue

  • 114 / 23

Start / End Page

  • E4676 - E4685

PubMed ID

  • 28533375

Pubmed Central ID

  • 28533375

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.1614943114

Language

  • eng