Rao R V, Ellerby H M, Bredesen D E
Buck Institute for Age Research, 8001 Redwood Boulevard, Novato, CA 94945, USA.
Cell Death Differ. 2004 Apr;11(4):372-80. doi: 10.1038/sj.cdd.4401378.
The endoplasmic reticulum (ER) regulates protein synthesis, protein folding and trafficking, cellular responses to stress and intracellular calcium (Ca(2+)) levels. Alterations in Ca(2+) homeostasis and accumulation of misfolded proteins in the ER cause ER stress that ultimately leads to apoptosis. Prolonged ER stress is linked to the pathogenesis of several different neurodegenerative disorders. Apoptosis is a form of cell death that involves the concerted action of a number of intracellular signaling pathways including members of the caspase family of cysteine proteases. The two main apoptotic pathways, the death receptor ('extrinsic') and mitochondrial ('intrinsic') pathways, are activated by caspase-8 and -9, respectively, both of which are found in the cytoplasm. Recent studies point to the ER as a third subcellular compartment implicated in apoptotic execution. Here, we review evidence for the contribution of various cellular molecules that contribute to ER stress and subsequent cellular death. It is hoped that dissection of the molecular components and pathways that alter ER structure and function and ultimately promote cellular death will provide a framework for understanding degenerative disorders that feature misfolded proteins.
内质网（ER）调节蛋白质合成、蛋白质折叠与运输、细胞应激反应以及细胞内钙（Ca(2+)）水平。Ca(2+)稳态的改变以及内质网中错误折叠蛋白质的积累会引发内质网应激，最终导致细胞凋亡。长期内质网应激与多种不同神经退行性疾病的发病机制相关。细胞凋亡是一种细胞死亡形式，涉及许多细胞内信号通路的协同作用，包括半胱氨酸蛋白酶caspase家族的成员。两条主要的凋亡途径，即死亡受体（“外在”）途径和线粒体（“内在”）途径，分别由caspase-8和-9激活，这两种蛋白酶均存在于细胞质中。最近的研究表明内质网是参与凋亡执行的第三个亚细胞区室。在此，我们综述了各种细胞分子对内质网应激及随后细胞死亡作用的证据。希望剖析改变内质网结构和功能并最终促进细胞死亡的分子成分和途径，将为理解以错误折叠蛋白质为特征的退行性疾病提供一个框架。
