Parkinson's disease (PD) is the most common neurodegenerative movement disease. It is featured by abnormal alpha-synuclein (α-syn) aggregation in dopaminergic neurons in the substantia nigra. Macroautophagy (autophagy) is an evolutionarily conserved cellular process for degradation of cellular contents, including protein aggregates, to maintain cellular homeostasis. Corynoxine B (Cory B), a natural alkaloid isolated from Uncaria rhynchophylla (Miq.) Jacks., has been reported to promote the clearance of α-syn in cell models by inducing autophagy. However, the molecular mechanism by which Cory B induces autophagy is not known, and the α-syn-lowering activity of Cory B has not been verified in animal models. Here, we report that Cory B enhanced the activity of Beclin 1/VPS34 complex and increased autophagy by promoting the interaction between Beclin 1 and HMGB1/2. Depletion of HMGB1/2 impaired Cory B-induced autophagy. We showed for the first time that, similar to HMGB1, HMGB2 is also required for autophagy and depletion of HMGB2 decreased autophagy levels and phosphatidylinositol 3-kinase III activity both under basal and stimulated conditions. By applying cellular thermal shift assay, surface plasmon resonance, and molecular docking, we confirmed that Cory B directly binds to HMGB1/2 near the C106 site. Furthermore, in vivo studies with a wild-type α-syn transgenic drosophila model of PD and an A53T α-syn transgenic mouse model of PD, Cory B enhanced autophagy, promoted α-syn clearance and improved behavioral abnormalities. Taken together, the results of this study reveal that Cory B enhances phosphatidylinositol 3-kinase III activity/autophagy by binding to HMGB1/2 and that this enhancement is neuroprotective against PD.

帕金森病（PD）是最常见的神经退行性运动疾病。其特征是黑质多巴胺能神经元中异常的 α-突触核蛋白 ( α -syn) 聚集。巨自噬（自噬）是一种进化上保守的细胞过程，用于降解细胞内容物（包括蛋白质聚集体），以维持细胞稳态。Corynoxine B (Cory B) 是一种从钩藤( Uncaria rhynchophylla (Miq.) Jacks.) 中分离出来的天然生物碱，据报道可通过诱导自噬促进细胞模型中α - syn 的清除。然而，Cory B 诱导自噬的分子机制尚不清楚，α- Cory B 的 syn 降低活性尚未在动物模型中得到验证。在此，我们报道 Cory B 通过促进 Beclin 1 和 HMGB1/2 之间的相互作用来增强 Beclin 1/VPS34 复合物的活性并增加自噬。HMGB1/2 的耗竭会损害 Cory B 诱导的自噬。我们首次表明，与 HMGB1 类似，HMGB2 也是自噬所必需的，并且 HMGB2 的消耗会降低基础条件和刺激条件下的自噬水平和磷脂酰肌醇 3-激酶 III 活性。通过应用细胞热位移测定、表面等离子共振和分子对接，我们证实Cory B直接与C106位点附近的HMGB1/2结合。此外，使用PD的野生型α -syn转基因果蝇模型和A53T α进行体内研究PD-syn 转基因小鼠模型，Cory B 增强自噬，促进α -syn 清除并改善行为异常。总而言之，这项研究的结果表明，Cory B 通过与 HMGB1/2 结合来增强磷脂酰肌醇 3-激酶 III 活性/自噬，并且这种增强对 PD 具有神经保护作用。