帕金森病（PD）是第二常见的神经退行性疾病，其患病率正在增加。目前,没有有效的PD治疗方法。海洋衍生的天然化合物由于其独特的结构和多样化的活性而被认为是发现新药的重要资源。在这项研究中,四氢乌兰光苷(TAG)，从海洋海绵中分离出来的聚酮化合物，发现对MPTP/MPP诱导的神经毒性具有明显的神经保护作用。RNA测序分析和代谢组学显示TAG显著改善PD模型中的脂质代谢紊乱。进一步的研究表明，TAG显着降低了脂滴（LD）的积累，下调RUBCN的表达，并促进自噬通量。此外，Rubcn的条件性敲除显著减轻了PD样症状和LD的积累，同时阻断TAG的神经保护作用。总的来说，我们的结果首先表明，TAG，有希望的PD治疗候选药物，可以通过RUBCN-自噬途径抑制LD的积累，这突出了一种新颖有效的PD治疗策略。
Parkinson\'s disease (PD) is the second most common neurodegenerative disease, and its prevalence is increasing. Currently, no effective therapies for PD exist. Marine-derived natural compounds are considered important resources for the discovery of new drugs due to their distinctive structures and diverse activities. In this study, tetrahydroauroglaucin (TAG), a polyketide isolated from a marine sponge, was found to have notable neuroprotective effects on MPTP/MPP+-induced neurotoxicity. RNA sequencing analysis and metabolomics revealed that TAG significantly improved lipid metabolism disorder in PD models. Further investigation indicated that TAG markedly decreased the accumulation of lipid droplets (LDs), downregulated the expression of
RUBCN, and promoted autophagic flux. Moreover, conditional knockdown of
Rubcn notably attenuated PD-like symptoms and the accumulation of LDs, accompanied by blockade of the neuroprotective effect of TAG. Collectively, our results first indicated that TAG, a promising PD therapeutic candidate, could suppress the accumulation of LDs through the
RUBCN-autophagy pathway, which highlighted a novel and effective strategy for PD treatment.
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