Zhou Hefeng, Li Shengnan, Li Chuwen, Yang Xuanjun, Li Haitao, Zhong Hanbing, Lu Jia-Hong, Lee Simon Ming-Yuen
1State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China.
2Department of Biology, South University of Science and Technology, Shenzhen, China.
Aging Dis. 2020 May 9;11(3):559-574. doi: 10.14336/AD.2019.0612. eCollection 2020 May.
Parkinson's disease (PD), the second most common neurodegenerative disorder, is neuropathologically characterized by the loss of dopaminergic neurons in the (SNc) and the presence of Lewy bodies in surviving neurons. α-synuclein (α-syn) is the major component of Lewy bodies and its deposition in neurons is critical pathological event in the pathogenesis of PD. Herein, we reported that Oxyphylla A, a novel lead compound from the fruit of , significantly promoted α-syn degradation in a cellular PD model. When exploring the molecular pathways, we found that Oxyphylla A promoted α-syn degradation in a ubiquitin proteasome system (UPS)-dependent and autophagy-independent manner. We further confirmed that Oxyphylla A enhanced UPS activity by upregulating 20S subunit PSMB8 expression. A mechanism study revealed that Oxyphylla A activated the PKA/Akt/mTOR pathway to trigger PSMB8 expression and enhance UPS activity. Finally, we illustrated that Oxyphylla A alleviated the accumulation of both Triton-soluble and Triton-insoluble forms of α-syn and protected against α-syn-induced neurotoxicity in A53T α-syn transgenic mice. These findings suggest that the activation of UPS, via small molecular UPS enhancers including Oxyphylla A, may be a therapeutic strategy for intervention against PD and related diseases.
帕金森病（PD）是第二常见的神经退行性疾病，其神经病理学特征是黑质致密部（SNc）多巴胺能神经元的丧失以及存活神经元中路易小体的存在。α-突触核蛋白（α-syn）是路易小体的主要成分，其在神经元中的沉积是PD发病机制中的关键病理事件。在此，我们报道了从益智果实中提取的一种新型先导化合物益智仁A，在细胞PD模型中显著促进α-syn的降解。在探索分子途径时，我们发现益智仁A以泛素蛋白酶体系统（UPS）依赖且自噬非依赖的方式促进α-syn的降解。我们进一步证实，益智仁A通过上调20S亚基PSMB8的表达来增强UPS活性。机制研究表明，益智仁A激活PKA/Akt/mTOR途径以触发PSMB8表达并增强UPS活性。最后，我们证明益智仁A减轻了A53T α-syn转基因小鼠中Triton可溶性和Triton不溶性形式的α-syn的积累，并保护其免受α-syn诱导的神经毒性。这些发现表明，通过包括益智仁A在内的小分子UPS增强剂激活UPS，可能是干预PD及相关疾病的一种治疗策略。
