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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.
Highlights
The huntingtin N17 domain is a modulator of mutant huntingtin toxicity and is hypophosphorylated in Huntington’s disease (HD)
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)
To identify modulators of N17 phosphorylation of huntingtin, we used high-content analysis to screen a library of 133 natural compounds (Selleckchem) for their potential effects on the fluorescent signal pattern of anti–N17S13pS16p, an antibody recognizing N17 phosphorylated on S13 and S16
Summary
The huntingtin N17 domain is a modulator of mutant huntingtin toxicity and is hypophosphorylated in Huntington’s disease (HD). 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. We have since defined huntingtin as a component of the ataxia telangiectasia mutated (ATM) DNA damageresponse complex that accumulates at sites of DNA oxidative damage and as a scaffold for DNA-repair factors [5] Along with these newly defined functions, huntingtin has previously been implicated in vesicular and axonal trafficking, cell division, synaptic transmission, and the cell stress response [6,7,8,9,10,11]. N6FFA has been extensively studied [20] and annotated as a plant cytokine with biological effects in mammalian cells, including
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