Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada.
Department of Pharmacology, University of Alberta, Edmonton, AB T6G 2R3, Canada.
Proc Natl Acad Sci U S A. 2018 Jul 24;115(30):E7081-E7090. doi: 10.1073/pnas.1801772115. Epub 2018 Jul 9.
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.
亨廷顿病（HD）中，突变型亨廷顿蛋白毒性的调节剂——亨廷顿 N17 结构域发生低磷酸化。我们通过高通量分析寻找能够恢复 N17 磷酸化的化合物，筛选出的一种先导化合物为 N6-糠基腺嘌呤（N6FFA）。N6FFA 可保护 HD 模型神经元，且 N6FFA 可纠正 HD 小鼠模型的表型，消除皮质突变型亨廷顿蛋白包涵体。我们发现，N6FFA 可通过腺嘌呤磷酸核糖基转移酶（APRT）被回收为三磷酸形式，再由酪蛋白激酶 2（CK2）作为磷酸供体，从而恢复 N17 磷酸化水平。N6FFA 是氧化 DNA 损伤的天然产物。磷酸化的亨廷顿蛋白在诱导的 DNA 损伤部位，通过功能性重分布与 CK2、APRT 和 N6FFA DNA 加合物共定位。我们提出了一个模型，即在 DNA 损伤条件下低 ATP 应激时，该天然产物化合物通过 CK2 被回收为三磷酸底物，从而为信号转导提供磷酸化底物，对 HD 模型系统具有保护作用。
