HMGB1 Mediates Autophagy Dysfunction via Perturbing Beclin1-Vps34 Complex in Dopaminergic Cell Model.
HMGB1 Mediates Autophagy Dysfunction via Perturbing Beclin1-Vps34 Complex in Dopaminergic Cell Model.
复制标题
HMGB1 通过扰乱多巴胺能细胞模型中的 Beclin1-Vps34 复合物介导自噬功能障碍
DOI：
10.3389/fnmol.2017.00013
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发表时间：
2017
影响因子：
4.8
通讯作者：
Wang T
中科院分区：
文献类型：
--
作者：
Huang J;Yang J;Shen Y;Jiang H;Han C;Zhang G;Liu L;Xu X;Li J;Lin Z;Xiong N;Zhang Z;Xiong J;Wang T
帕金森病（Parkinson's disease，PD）是一种进行性神经退行性疾病，以多巴胺能神经元不可逆性丢失和神经元内α-突触核蛋白聚集为特征。高迁移率族蛋白B1（HMGB 1）参与了α-突触核蛋白（α-synuclein，α-synuclein）聚集诱导的自噬功能障碍，Beclin 1-vacuolar protein sorting 34（Vps 34）复合物在自噬的启动中起重要作用。然而，HMGB 1、α-synuclein和自噬之间的具体相互作用机制仍不清楚，特别是在PD的背景下。在本研究中，我们研究了HMGB 1和α-synuclein在鱼藤酮诱导的PD细胞模型中的相互作用及其在自噬通量中的作用。结果显示，鱼藤酮暴露后内源性HMGB 1的表达和胞浆易位升高。此外，HMGB 1还能与α-synuclein共定位并相互作用。HMGB 1可通过干扰Beclin 1-Vps 34复合物的形成，加重α-synuclein聚集诱导的自噬功能障碍。基于这些发现，我们认为HMGB 1通过与α-synuclein相互作用，干扰自噬过程，加剧蛋白聚集，最终推动多巴胺能神经元从发病到死亡，从而参与鱼藤酮诱导的多巴胺能细胞死亡。
Parkinson’s disease (PD), a progressive neurodegenerative disorder, is characterized by irreversible dopaminergic neuron loss and intra-neuronal α-synuclein aggregation. High mobility group box 1 (HMGB1) has been proven to be involved in autophagy dysfunction induced by α-synuclein accumulation, and the Beclin1-vacuolar protein sorting 34 (Vps34) complex is of great importance to the initiation of autophagy. Nevertheless, the concrete interaction mechanism between HMGB1, α-synuclein and autophagy remains elusive, especially in the context of PD. Here in this study, we investigated the interaction between HMGB1 and α-synuclein in rotenone-induced PD cell models and their roles in autophagy flux. Results revealed elevated expression and cytosolic translocation of endogenous HMGB1 upon rotenone exposure. Besides, HMGB1 was found to be able to co-localize and interact with α-synuclein. Moreover, it had also been proven that HMGB1 could aggravate α-synuclein aggregation induced autophagy dysfunction via perturbing Beclin1-Vps34 complex formation. Based on these findings, we propose that HMGB1 is involved in rotenone-induced dopaminergic cell death via interacting with α-synuclein, perturbing the autophagy process, aggravating protein aggregation and finally propelling dopaminergic neurons to move from morbidity to mortality.