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Research Article

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

Laura E. Bowie, Tamara Maiuri, Melanie Alpaugh, Michelle Gabriel, View ORCID ProfileNicolas Arbez, Danny Galleguillos, Claudia L. K. Hung, Shreya Patel, Jianrun Xia, Nicholas T. Hertz, Christopher A. Ross, David W. Litchfield, Simonetta Sipione, and View ORCID ProfileRay Truant
  1. aDepartment of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada;
  2. bDepartment of Pharmacology, University of Alberta, Edmonton, AB T6G 2R3, Canada;
  3. cDepartment of Biochemistry, Western University, London, ON N6A 3K7, Canada;
  4. dDivision of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore MD 21205;
  5. eMitokinin, LLC, New York, NY 10006

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PNAS July 24, 2018 115 (30) E7081-E7090; first published July 9, 2018; https://doi.org/10.1073/pnas.1801772115
Laura E. Bowie
aDepartment of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada;
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Tamara Maiuri
aDepartment of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada;
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Melanie Alpaugh
bDepartment of Pharmacology, University of Alberta, Edmonton, AB T6G 2R3, Canada;
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Michelle Gabriel
cDepartment of Biochemistry, Western University, London, ON N6A 3K7, Canada;
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Nicolas Arbez
dDivision of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore MD 21205;
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  • ORCID record for Nicolas Arbez
Danny Galleguillos
bDepartment of Pharmacology, University of Alberta, Edmonton, AB T6G 2R3, Canada;
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Claudia L. K. Hung
aDepartment of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada;
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Shreya Patel
aDepartment of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada;
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Jianrun Xia
aDepartment of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada;
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Nicholas T. Hertz
eMitokinin, LLC, New York, NY 10006
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Christopher A. Ross
dDivision of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore MD 21205;
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David W. Litchfield
cDepartment of Biochemistry, Western University, London, ON N6A 3K7, Canada;
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Simonetta Sipione
bDepartment of Pharmacology, University of Alberta, Edmonton, AB T6G 2R3, Canada;
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Ray Truant
aDepartment of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada;
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  • For correspondence: truantr@mcmaster.ca
  1. Edited by Nancy E. Kleckner, Harvard University, Cambridge, MA, and approved June 19, 2018 (received for review January 31, 2018)

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Significance

We have discovered a molecule derived from DNA-damage repair that can correct the lack of phosphorylation of mutant huntingtin, the cause of Huntington’s disease (HD). In a mouse model, treatment reverses HD-like disease, and we see the lowering of mutant huntingtin levels to normal. The mechanism of this molecule is that it is processed to make a signal for kinase activity essential for repairing DNA. This mechanism is critical when neurons are stressed and have very low or absent energy levels. We propose that this molecule is a type of signaling from DNA-damage repair that occurs at dangerously low ATP levels.

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 adducts 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.

  • DNA repair
  • oxidation
  • Huntington’s disease
  • neurodegeneration
  • high-content analysis

Footnotes

  • ↵1To whom correspondence should be addressed. Email: truantr{at}mcmaster.ca.
  • Author contributions: L.E.B., T.M., M.A., M.G., N.A., S.S., and R.T. designed research; L.E.B., T.M., M.A., M.G., N.A., D.G., C.L.K.H., S.P., and J.X. performed research; T.M., M.A., M.G., N.A., D.G., C.L.K.H., S.P., J.X., and N.T.H. contributed new reagents/analytic tools; L.E.B., T.M., M.A., M.G., N.A., N.T.H., C.A.R., D.W.L., and R.T. analyzed data; and L.E.B., T.M., S.S., and R.T. wrote the paper.

  • Conflict of interest statement: R.T. is on the Scientific Advisory Board and is a minor shareholder of Mitokinin, LLC. N.T.H. is the Chief Scientific Officer of Mitokinin, LLC.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1801772115/-/DCSupplemental.

Published under the PNAS license.

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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
Proceedings of the National Academy of Sciences Jul 2018, 115 (30) E7081-E7090; DOI: 10.1073/pnas.1801772115

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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
Proceedings of the National Academy of Sciences Jul 2018, 115 (30) E7081-E7090; DOI: 10.1073/pnas.1801772115
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