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.  Farmer; Vijay  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

doi:10.1073/pnas.1614943114

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

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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 TNFα. Together, our results demonstrate a multifaceted protective potential of NRF2 signaling in key cell types relevant to HD pathology.

Original language	English
Pages (from-to)	e4676-e4685
Number of pages	10
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	114
Issue number	23
Early online date	22 May 2017
DOIs	https://doi.org/10.1073/pnas.1614943114
Publication status	Published - 6 Jun 2017

Keywords

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

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10.1073/pnas.1614943114

Author Accepted ManuscriptAccepted author manuscript, 7.23 MB

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Projects

1 Finished

The Spatiotemporal Regulation of the Keap1/Nrf2 Pathway (Joint with University College London)

Dinkova-Kostova, A.

Biotechnology and Biological Sciences Research Council

30/09/14 → 27/02/18

Project: Research

Profiles

Dinkova-Kostova, Albena

Cellular Medicine - Professor (Teaching and Research) & Professor of Chemical Biology

Person: Academic

Cite this

Quinti, L., Dayalan Naidu, S., Träge, U., Chen, X., Kegel-Gleason, K., Lleres, D., Connolly, C., Chopra, V., Low, C., Moniot, S., Sapp, E., Tousley, A. R., Vodicka, P., Van Kanegan, M. J., Kaltenbach, L. S., Crawford, L. A., Fuszard, M., Higgins, M., Miller, J. R. C., ... Kazantsev, A. G. (2017). KEAP1-modifying small molecule reveals muted NRF2 signaling responses in neural stem cells from Huntington's disease patients. Proceedings of the National Academy of Sciences of the United States of America, 114(23), e4676-e4685. https://doi.org/10.1073/pnas.1614943114

Quinti, Luisa ; Dayalan Naidu, Sharadha ; Träge, Ulrike ; Chen, Xiqun ; Kegel-Gleason, Kimberly ; Lleres, David ; Connolly, Colúm ; Chopra, Vanita ; Low, Cho ; Moniot, Sebastien ; 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 ; 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. 2017 ; Vol. 114, No. 23. pp. e4676-e4685.

@article{014b203f43a74474862618a26cdf1094,

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

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 TNFα. Together, our results demonstrate a multifaceted protective potential of NRF2 signaling in key cell types relevant to HD pathology.",

keywords = "Huntington{\textquoteright}s disease, KEAP1/NRF2/ARE, NRF2 inducer, Anti-Inflammatory Responses, Human Neural Stem Cells",

author = "Luisa Quinti and {Dayalan Naidu}, Sharadha and Ulrike Tr{\"a}ge and Xiqun Chen and Kimberly Kegel-Gleason and David Lleres and Col{\'u}m Connolly and Vanita Chopra and Cho Low and Sebastien Moniot and Ellen Sapp and Tousley, {Adelaide R} and Petr Vodicka and {Van Kanegan}, {Michael J.} and Kaltenbach, {Linda S.} and Crawford, {Lisa A} and Matthew Fuszard and Maureen Higgins and Miller, {James R.C.} and Farmer, {Ruth E.} and Vijay Potluri and Susanta Samajdar and Lisa Meisel and Ningzhe Zhang and Andrew Snyder and Ross Stein and Hersch, {Steven M.} and Ellerby, {Lisa M.} and Eranthie Weerapana and Schwarzschild, {Michael A.} and Clemens Steegborn and Leavitt, {Blair R.} and Alexei Degterev and Tabrizi, {Sarah J.} and Lo, {Donald C.} and Marian DiFiglia and Thompson, {Leslie M.} and Albena Dinkova-Kostova and Kazantsev, {Aleksey G.}",

note = "This work was supported by grants from the NIH U01-NS066912, R01NS04528, and NIGMS grant GM080356, the Biotechnology and Biological Sciences Research Council (BB/J007498/1, BB/L01923X/1), and Cancer Research UK (C20953/A18644). We also acknowledge support from RJG foundation to L.Q, X.C., and A.G.K and CHDI Foundation to M.D. and K.K., Alzheimer Forschung Initiative grant 14834 to C.S., and NINDS NS100529 to LME. ",

year = "2017",

month = jun,

day = "6",

doi = "10.1073/pnas.1614943114",

language = "English",

volume = "114",

pages = "e4676--e4685",

journal = "Proceedings of the National Academy of Sciences",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "23",

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Quinti, L, Dayalan Naidu, S, Träge, U, Chen, X, Kegel-Gleason, K, Lleres, 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, A & Kazantsev, AG 2017, 'KEAP1-modifying small molecule reveals muted NRF2 signaling responses in neural stem cells from Huntington's disease patients', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 23, pp. e4676-e4685. https://doi.org/10.1073/pnas.1614943114

KEAP1-modifying small molecule reveals muted NRF2 signaling responses in neural stem cells from Huntington's disease patients. / Quinti, Luisa; Dayalan Naidu, Sharadha; Träge, Ulrike ; Chen, Xiqun ; Kegel-Gleason, Kimberly ; Lleres, David; Connolly, Colúm ; Chopra, Vanita ; Low, Cho ; Moniot, Sebastien; 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; Kazantsev, Aleksey G. (Lead / Corresponding author).

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 23, 06.06.2017, p. e4676-e4685.

Research output: Contribution to journal › Article

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 - Dayalan Naidu, Sharadha

AU - Träge, Ulrike

AU - Chen, Xiqun

AU - Kegel-Gleason, Kimberly

AU - Lleres, David

AU - Connolly, Colúm

AU - Chopra, Vanita

AU - Low, Cho

AU - Moniot, Sebastien

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

AU - Kazantsev, Aleksey G.

N1 - This work was supported by grants from the NIH U01-NS066912, R01NS04528, and NIGMS grant GM080356, the Biotechnology and Biological Sciences Research Council (BB/J007498/1, BB/L01923X/1), and Cancer Research UK (C20953/A18644). We also acknowledge support from RJG foundation to L.Q, X.C., and A.G.K and CHDI Foundation to M.D. and K.K., Alzheimer Forschung Initiative grant 14834 to C.S., and NINDS NS100529 to LME.

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 TNFα. 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 TNFα. Together, our results demonstrate a multifaceted protective potential of NRF2 signaling in key cell types relevant to HD pathology.

KW - Huntington’s disease

KW - KEAP1/NRF2/ARE

KW - NRF2 inducer

KW - Anti-Inflammatory Responses

KW - Human Neural Stem Cells

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U2 - 10.1073/pnas.1614943114

DO - 10.1073/pnas.1614943114

M3 - Article

C2 - 28533375

VL - 114

SP - e4676-e4685

JO - Proceedings of the National Academy of Sciences

JF - Proceedings of the National Academy of Sciences

SN - 0027-8424

IS - 23

ER -