内质网应激中GRP78和ATF4-CHOP-Puma信号通路与帕金森病的关系及其治疗靶点的研究进展

Progress on the Involvement of GRP78 and ATF_4–CHOP–Puma Signaling Pathway in Endoplasmic Reticulum Stress and Parkinson's Disease

内质网是真核细胞中重要的细胞器之一,与维持细胞稳态关系密切。当缺乏葡萄糖、缺氧、体内钙平衡紊乱或者发生氧化应激时,会引起细胞内未折叠蛋白或错误折叠蛋白的积累,导致内质网应激。帕金森病是一种慢性进行性脑变性疾病,典型的病理变化是黑质纹状体多巴胺能神经细胞变性丢失导致的多巴胺神经递质缺乏。目前对帕金森病的治疗多为缓解症状,但不能阻止疾病的进展。通过对内质网应激中的信号通路的研究发现:在帕金森病的发病过程中,多巴胺能神经元的选择性死亡与内质网应激有关。内质网应激过程中的中心调节因子:葡萄糖调节蛋白78(glucose regulated protein 78,GRP78)及其下游ATF4-CHOP-Puma信号通路与帕金森病的发病过程有密切的联系,本文对GRP78及其下游ATF4-CHOP-Puma信号通路近些年来的研究进展进行综述,以期为帕金森病的治疗提供新的靶点和思路。

Endoplasmic reticulum is one of the important organelles in eukaryotic cells, and it is closely related to the cellular homeostasis state. Glucose shortage, hypoxia, calcium imbalance and oxidative stress all can lead to the accumulation of unfolded or misfolded proteins in the cells,which will lead to endoplasmic reticulum stress. Parkinson＇s disease is a chronic progressive neurodegenerative disease, with the typical pathological changes being the lack of the neurotransmitter dopamine resulting from the degeneration and loss of the dopaminergic nerve cells in the substantia nigra striatum. Current treatments of Parkinson＇s disease is to relieve the symptoms rather than prevent the progression of the disease. Recent research suggests that the selective death of dopaminergic neurons is associated with endoplasmic reticulum stress in the process of the Parkinson＇s disease. The central modulating factors of endoplasmic retieulum stress, i.e. glucose regulated protein 78 （GRP78） and the downstream ATF4-CHOP- Puma signaling pathway, are closely linked to the progress of the Parkinson＇s disease. This review summarized recent developments of the GRP78 and its downstream ATF4-CHOP-Puma signaling pathways, in the hope of providing information for the potential new targets in the treatment of Parkinson＇s disease.