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

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


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 languageEnglish (US)
Pages (from-to)E7081-E7090
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number30
StatePublished - Jul 24 2018


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

ASJC Scopus subject areas

  • General


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