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

Proc Natl Acad Sci U S A. 2018 Jul 24;115(30):E7081-E7090. doi: 10.1073/pnas.1801772115. Epub 2018 Jul 9.

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.

Keywords: DNA repair; Huntington’s disease; high-content analysis; neurodegeneration; oxidation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine Phosphoribosyltransferase / genetics
  • Adenine Phosphoribosyltransferase / metabolism
  • Adenine* / analogs & derivatives
  • Adenine* / pharmacokinetics
  • Adenine* / pharmacology
  • Animals
  • Casein Kinase II / genetics
  • Casein Kinase II / metabolism
  • Cell Line, Transformed
  • DNA Adducts / genetics
  • DNA Adducts / metabolism*
  • DNA Damage*
  • Disease Models, Animal
  • Humans
  • Huntington Disease / drug therapy*
  • Huntington Disease / genetics
  • Huntington Disease / metabolism
  • Huntington Disease / pathology
  • Mice
  • Mice, Transgenic
  • Neurons / metabolism*
  • Neurons / pathology
  • Phosphorylation / drug effects
  • Phosphorylation / genetics
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics

Substances

  • DNA Adducts
  • Adenine Phosphoribosyltransferase
  • Casein Kinase II
  • Adenine