Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei, 430000, China.
Mol Neurobiol. 2018 Jun;55(6):4825-4833. doi: 10.1007/s12035-017-0686-0. Epub 2017 Jul 22.
Parkinson's disease (PD) is the most common movement disorder disease, and its pathological feature is the degenerative loss of dopaminergic neurons in the substantia nigra compacta (SNc). In this study, we investigated whether distinct stress conditions target F-box protein Fbw7β via converging mechanisms. Our results showed that the 6-hyroxydopamine (6-OHDA), which causes PD in animals' models, led to decreased stability of Fbw7β in DA neuronal SN4741 cells. Further experiments suggested that oxidized Fbw7β bound to heat-shock cognate protein 70 kDa, the key regulator for chaperone-mediated autophagy (CMA), at a higher affinity. Oxidative stress also increased the level of lysosomal-associated membrane protein 2A (LAMP2A), the rate-limiting receptor for CMA substrate flux, and stimulated CMA activity. These changes resulted in accelerated degradation of Fbw7β. 6-OHDA induced Fbw7β oxidation and increased LAMP2A in the SNc region of the mouse models. Consistently, the levels of oxidized Fbw7β were higher in postmortem PD brains compared with the controls. These findings for the first time revealed the specific mechanism of ubiquitin ligases, oxidative stress, and CMA-mediated protein degradation, to provide a new theoretical basis for further clarifying the mechanism of PD.
帕金森病（PD）是最常见的运动障碍性疾病，其病理特征是黑质致密部（SNc）多巴胺能神经元的退行性丧失。在这项研究中，我们研究了不同的应激条件是否通过趋同机制靶向 F-box 蛋白 Fbw7β。我们的结果表明，6-羟多巴胺（6-OHDA）会导致动物模型中的 PD，导致 DA 神经元 SN4741 细胞中 Fbw7β 的稳定性降低。进一步的实验表明，氧化的 Fbw7β以更高的亲和力与热休克同源蛋白 70 kDa（伴侣介导的自噬（CMA）的关键调节剂）结合。氧化应激还增加了溶酶体相关膜蛋白 2A（LAMP2A）的水平，LAMP2A 是 CMA 底物通量的限速受体，并刺激了 CMA 活性。这些变化导致 Fbw7β的降解加速。6-OHDA 在小鼠模型的 SNc 区域诱导 Fbw7β氧化和 LAMP2A 增加。一致的是，与对照组相比，帕金森病死后大脑中氧化的 Fbw7β水平更高。这些发现首次揭示了泛素连接酶、氧化应激和 CMA 介导的蛋白质降解的特定机制，为进一步阐明 PD 的机制提供了新的理论依据。
