TY - JOUR
T1 - KEAP1-modifying small molecule reveals muted NRF2 signaling responses in neural stem cells from Huntington's disease patients
AU - Quinti, Luisa
AU - Naidu, Sharadha Dayalan
AU - Träger, Ulrike
AU - Chen, Xiqun
AU - Kegel-Gleason, Kimberly
AU - Llères, David
AU - Connolly, Colúm
AU - Chopra, Vanita
AU - Low, Cho
AU - Moniot, Sébastien
AU - Sapp, Ellen
AU - Tousley, Adelaide R.
AU - Vodicka, Petr
AU - Van Kanegan, Michael J.
AU - Kaltenbach, Linda S.
AU - Crawford, Lisa A.
AU - Fuszard, Matthew
AU - Higgins, Maureen
AU - Miller, James R.C.
AU - Farmer, Ruth E.
AU - Potluri, Vijay
AU - Samajdar, Susanta
AU - Meisel, Lisa
AU - Zhang, Ningzhe
AU - Snyder, Andrew
AU - Stein, Ross
AU - Hersch, Steven M.
AU - Ellerby, Lisa M.
AU - Weerapana, Eranthie
AU - Schwarzschild, Michael A.
AU - Steegborn, Clemens
AU - Leavitt, Blair R.
AU - Degterev, Alexei
AU - Tabrizi, Sarah J.
AU - Lo, Donald C.
AU - DiFiglia, Marian
AU - Thompson, Leslie M.
AU - Dinkova-Kostova, Albena T.
AU - Kazantsev, Aleksey G.
PY - 2017/6/6
Y1 - 2017/6/6
N2 - 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 TNFa. Together, our results demonstrate a multifaceted protective potential of NRF2 signaling in key cell types relevant to HD pathology.
AB - 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 TNFa. Together, our results demonstrate a multifaceted protective potential of NRF2 signaling in key cell types relevant to HD pathology.
KW - Antiinflammatory responses
KW - Human neural stem cells
KW - Huntington's disease
KW - KEAP1/NRF2/ARE signaling
KW - NRF2 inducer
UR - http://www.scopus.com/inward/record.url?scp=85020286880&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85020286880&partnerID=8YFLogxK
U2 - 10.1073/pnas.1614943114
DO - 10.1073/pnas.1614943114
M3 - Article
C2 - 28533375
AN - SCOPUS:85020286880
SN - 0027-8424
VL - 114
SP - E4676-E4685
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 23
ER -