α‑synuclein induces apoptosis of astrocytes by causing dysfunction of the endoplasmic reticulum‑Golgi compartment.
α‑synuclein induces apoptosis of astrocytes by causing dysfunction of the endoplasmic reticulum‑Golgi compartment.
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DOI：
10.3892/mmr.2018.9002
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发表时间：
2018-07
影响因子：
3.4
通讯作者：
Wang C
中科院分区：
文献类型：
--
作者：
Liu M;Qin L;Wang L;Tan J;Zhang H;Tang J;Shen X;Tan L;Wang C
虽然以往的研究表明，野生型或突变型α-突触核蛋白(α-SYN)的过表达可通过多种不同的机制诱导细胞死亡，包括氧化应激、泛素-蛋白酶体降解系统功能障碍、线粒体损伤和内质网应激，但研究兴趣主要集中在神经元。然而，越来越多的证据表明，星形胶质细胞可能参与了早期的变化，以及帕金森病(PD)的进展，尽管α-SYN在星形胶质细胞中的作用尚未得到广泛研究。本研究发现星形胶质细胞内突变型α-SYN(A53T和A30P)通过蛋白激酶类ER激酶/真核细胞翻译起始因子2α信号通路触发内质网应激。通过CCAAT增强子结合蛋白同源蛋白介导的途径诱导星形胶质细胞的凋亡。此外，在此过程中还观察到高尔基体碎裂。另一方面，在原代神经元-星形胶质细胞共培养体系中，α-SYN的过表达显著降低了胶质细胞源性神经营养因子的水平，并部分抑制了神经突起的生长。尽管目前缺乏直接的证据，但有人认为，星形胶质细胞过度表达α-SYN的内质网高尔基体功能障碍可能导致胶质细胞源性神经营养因子水平下降，进而抑制轴突生长。综上所述，本研究结果从星形胶质细胞的角度对帕金森病的发病机制提供了进一步的见解，可能为未来帕金森病的诊断和治疗提供新的策略。
Although previous work has demonstrated that the overexpression of wild-type or mutant α-synuclein (α-syn) can induce cell death via a number of different mechanisms, including oxidative stress, dysfunction of the ubiquitin-proteasome degradation system, mitochondrial damage and endoplasmic reticulum (ER) stress, research interest has primarily focused on neurons. However, there is accumulating evidence that suggests that astrocytes may be involved in the earliest changes, as well as the progression of Parkinson's disease (PD), though the role of α-syn in astrocytes has not been widely studied. In the present study, it was revealed that the mutant α-syn (A53T and A30P) in astrocytes triggered ER stress via the protein kinase RNA-like ER kinase/eukaryotic translation initiation factor 2α signaling pathway. Astrocyte apoptosis was induced through a CCAAT-enhancer-binding protein homologous protein-mediated pathway. In addition, Golgi fragmentation was observed in the process. On the other hand, it was also demonstrated, in a primary neuronal-astroglial co-culture system, that the overexpression of α-syn significantly decreased the levels of glia-derived neurotrophic factor (GDNF) and partly inhibited neurite outgrowth. Although direct evidence is currently lacking, it was proposed that dysfunction of the ER-Golgi compartment in astrocytes overexpressing α-syn may lead to a decline of GDNF levels, which in turn would suppress neurite outgrowth. Taken together, the results of the present study offer further insights into the pathogenesis of PD from the perspective of astrocytes, which may provide novel strategies for the diagnosis and treatment of PD in the future.
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