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N6-Furfuryladenine is protective in Huntington’s disease models by signaling huntingtin phosphorylation
Authors
Melanie Alpaugh
Nicolas Arbez
+12 more
Laura E. Bowie
Michelle Gabriel
Danny Galleguillos
Nicholas T. Hertz
Claudia L.K. Hung
David W. Litchfield
Tamara Maiuri
Shreya Patel
Christopher A. Ross
Simonetta Sipione
Ray Truant
Jianrun Xia
Publication date
24 July 2018
Publisher
Scholarship@Western
Abstract
© 2018 National Academy of Sciences. All Rights Reserved. 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
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Last time updated on 20/03/2021