N6-Furfuryladenine is protective in Huntington’s disease models by signaling huntingtin phosphorylation

Laura E. Bowie; Tamara Maiuri; Melanie Alpaugh; Michelle Gabriel; Nicolas Arbez; Danny Galleguillos; Claudia L.K. Hung; Shreya Patel; Jianrun Xia; Nicholas T. Hertz; Christopher A. Ross; David W. Litchfield; Simonetta Sipione; Ray Truant

doi:10.1073/pnas.1801772115

N6-Furfuryladenine is protective in Huntington’s disease models by signaling huntingtin phosphorylation

Laura E. Bowie, Tamara Maiuri, Melanie Alpaugh, Michelle Gabriel, Nicolas Arbez, Danny Galleguillos, Claudia L.K. Hung, Shreya Patel, Jianrun Xia, Nicholas T. Hertz, Christopher A. Ross, David W. Litchfield, Simonetta Sipione, Ray Truant

School of Medicine

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

The huntingtin N17 domain is a modulator of mutant huntingtin toxicity and is hypophosphorylated in Huntington’s disease (HD). We conducted high-content analysis to find compounds that could restore N17 phosphorylation. One lead compound from this screen was N6-furfuryladenine (N6FFA). N6FFA was protective in HD model neurons, and N6FFA treatment of an HD mouse model corrects HD phenotypes and eliminates cortical mutant huntingtin inclusions. We show that N6FFA restores N17 phosphorylation levels by being salvaged to a triphosphate form by adenine phosphoribosyltransferase (APRT) and used as a phosphate donor by casein kinase 2 (CK2). N6FFA is a naturally occurring product of oxidative DNA damage. Phosphorylated huntingtin functionally redistributes and colocalizes with CK2, APRT, and N6FFA DNA ad-ducts at sites of induced DNA damage. We present a model in which this natural product compound is salvaged to provide a triphosphate substrate to signal huntingtin phosphorylation via CK2 during low-ATP stress under conditions of DNA damage, with protective effects in HD model systems.

Original language	English (US)
Pages (from-to)	E7081-E7090
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	115
Issue number	30
DOIs	https://doi.org/10.1073/pnas.1801772115
State	Published - Jul 24 2018

Keywords

DNA repair
High-content analysis
Huntington’s disease
Neurodegeneration
Oxidation

ASJC Scopus subject areas

General

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10.1073/pnas.1801772115

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Bowie, L. E., Maiuri, T., Alpaugh, M., Gabriel, M., Arbez, N., Galleguillos, D., Hung, C. L. K., Patel, S., Xia, J., Hertz, N. T., Ross, C. A., Litchfield, D. W., Sipione, S., & Truant, R. (2018). N6-Furfuryladenine is protective in Huntington’s disease models by signaling huntingtin phosphorylation. Proceedings of the National Academy of Sciences of the United States of America, 115(30), E7081-E7090. https://doi.org/10.1073/pnas.1801772115

Bowie, LE, Maiuri, T, Alpaugh, M, Gabriel, M, Arbez, N, Galleguillos, D, Hung, CLK, Patel, S, Xia, J, Hertz, NT, Ross, CA, Litchfield, DW, Sipione, S & Truant, R 2018, 'N6-Furfuryladenine is protective in Huntington’s disease models by signaling huntingtin phosphorylation', Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 30, pp. E7081-E7090. https://doi.org/10.1073/pnas.1801772115

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title = "N6-Furfuryladenine is protective in Huntington{\textquoteright}s disease models by signaling huntingtin phosphorylation",

abstract = "The huntingtin N17 domain is a modulator of mutant huntingtin toxicity and is hypophosphorylated in Huntington{\textquoteright}s disease (HD). We conducted high-content analysis to find compounds that could restore N17 phosphorylation. One lead compound from this screen was N6-furfuryladenine (N6FFA). N6FFA was protective in HD model neurons, and N6FFA treatment of an HD mouse model corrects HD phenotypes and eliminates cortical mutant huntingtin inclusions. We show that N6FFA restores N17 phosphorylation levels by being salvaged to a triphosphate form by adenine phosphoribosyltransferase (APRT) and used as a phosphate donor by casein kinase 2 (CK2). N6FFA is a naturally occurring product of oxidative DNA damage. Phosphorylated huntingtin functionally redistributes and colocalizes with CK2, APRT, and N6FFA DNA ad-ducts at sites of induced DNA damage. We present a model in which this natural product compound is salvaged to provide a triphosphate substrate to signal huntingtin phosphorylation via CK2 during low-ATP stress under conditions of DNA damage, with protective effects in HD model systems.",

keywords = "DNA repair, High-content analysis, Huntington{\textquoteright}s disease, Neurodegeneration, Oxidation",

author = "Bowie, {Laura E.} and Tamara Maiuri and Melanie Alpaugh and Michelle Gabriel and Nicolas Arbez and Danny Galleguillos and Hung, {Claudia L.K.} and Shreya Patel and Jianrun Xia and Hertz, {Nicholas T.} and Ross, {Christopher A.} and Litchfield, {David W.} and Simonetta Sipione and Ray Truant",

note = "Funding Information: ACKNOWLEDGMENTS. This study was supported by Canadian Institutes of Health Research Project Grant MOP-119391, The Krembil Foundation, and the Huntington Society of Canada. Publisher Copyright: {\textcopyright} 2018 National Academy of Sciences. All Rights Reserved.",

year = "2018",

month = jul,

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doi = "10.1073/pnas.1801772115",

language = "English (US)",

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T1 - N6-Furfuryladenine is protective in Huntington’s disease models by signaling huntingtin phosphorylation

AU - Bowie, Laura E.

AU - Maiuri, Tamara

AU - Alpaugh, Melanie

AU - Gabriel, Michelle

AU - Arbez, Nicolas

AU - Galleguillos, Danny

AU - Hung, Claudia L.K.

AU - Patel, Shreya

AU - Xia, Jianrun

AU - Hertz, Nicholas T.

AU - Ross, Christopher A.

AU - Litchfield, David W.

AU - Sipione, Simonetta

AU - Truant, Ray

N1 - Funding Information: ACKNOWLEDGMENTS. This study was supported by Canadian Institutes of Health Research Project Grant MOP-119391, The Krembil Foundation, and the Huntington Society of Canada. Publisher Copyright: © 2018 National Academy of Sciences. All Rights Reserved.

PY - 2018/7/24

Y1 - 2018/7/24

N2 - The huntingtin N17 domain is a modulator of mutant huntingtin toxicity and is hypophosphorylated in Huntington’s disease (HD). We conducted high-content analysis to find compounds that could restore N17 phosphorylation. One lead compound from this screen was N6-furfuryladenine (N6FFA). N6FFA was protective in HD model neurons, and N6FFA treatment of an HD mouse model corrects HD phenotypes and eliminates cortical mutant huntingtin inclusions. We show that N6FFA restores N17 phosphorylation levels by being salvaged to a triphosphate form by adenine phosphoribosyltransferase (APRT) and used as a phosphate donor by casein kinase 2 (CK2). N6FFA is a naturally occurring product of oxidative DNA damage. Phosphorylated huntingtin functionally redistributes and colocalizes with CK2, APRT, and N6FFA DNA ad-ducts at sites of induced DNA damage. We present a model in which this natural product compound is salvaged to provide a triphosphate substrate to signal huntingtin phosphorylation via CK2 during low-ATP stress under conditions of DNA damage, with protective effects in HD model systems.

AB - The huntingtin N17 domain is a modulator of mutant huntingtin toxicity and is hypophosphorylated in Huntington’s disease (HD). We conducted high-content analysis to find compounds that could restore N17 phosphorylation. One lead compound from this screen was N6-furfuryladenine (N6FFA). N6FFA was protective in HD model neurons, and N6FFA treatment of an HD mouse model corrects HD phenotypes and eliminates cortical mutant huntingtin inclusions. We show that N6FFA restores N17 phosphorylation levels by being salvaged to a triphosphate form by adenine phosphoribosyltransferase (APRT) and used as a phosphate donor by casein kinase 2 (CK2). N6FFA is a naturally occurring product of oxidative DNA damage. Phosphorylated huntingtin functionally redistributes and colocalizes with CK2, APRT, and N6FFA DNA ad-ducts at sites of induced DNA damage. We present a model in which this natural product compound is salvaged to provide a triphosphate substrate to signal huntingtin phosphorylation via CK2 during low-ATP stress under conditions of DNA damage, with protective effects in HD model systems.

KW - DNA repair

KW - High-content analysis

KW - Huntington’s disease

KW - Neurodegeneration

KW - Oxidation

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JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 30

ER -

N6-Furfuryladenine is protective in Huntington’s disease models by signaling huntingtin phosphorylation

Abstract

Keywords

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