Institute of Biomedicine/Biochemistry and Developmental Biology, University of Helsinki, Biomedicum Helsinki, Helsinki, Finland.
Cell Death Dis. 2013 May 23;4(5):e646. doi: 10.1038/cddis.2013.170.
Alterations in mitochondria and increased oxidative stress are associated with the disease progression in Huntington's disease (HD). Endoplasmic reticulum (ER) stress and oxidative damage are linked through the close communication between the ER and mitochondria. Sigma-1 receptor (Sig-1R) is a chaperone protein in the ER that is involved in ER stress regulation, but little is known about its role in HD or the mechanisms for cell protection. Here we show that the Sig-1R agonist, PRE084 increases cell survival and counteracts the deleterious effects caused by N-terminal mutant huntingtin proteins in neuronal PC6.3 cells. Particularly, PRE084 increased the levels of cellular antioxidants by activating the NF-κB pathway that is compromised by the expression of mutant huntingtin proteins. These results show that the Sig-1R agonist has beneficial effects in models of HD and that compounds affecting the Sig-1R may be promising targets for future drug development in HD.
线粒体的改变和氧化应激的增加与亨廷顿病（HD）的疾病进展有关。内质网（ER）应激和氧化损伤通过 ER 和线粒体之间的紧密通讯联系在一起。Sigma-1 受体（Sig-1R）是 ER 中的一种伴侣蛋白，参与 ER 应激调节，但对其在 HD 中的作用或细胞保护机制知之甚少。在这里，我们发现 Sig-1R 激动剂 PRE084 可增加细胞存活率，并对抗由神经元 PC6.3 细胞中 N 端突变 huntingtin 蛋白引起的有害作用。特别是，PRE084 通过激活 NF-κB 通路增加了细胞内抗氧化剂的水平，而突变 huntingtin 蛋白的表达会损害 NF-κB 通路。这些结果表明，Sig-1R 激动剂在 HD 模型中具有有益的作用，并且影响 Sig-1R 的化合物可能是 HD 未来药物开发的有前途的靶点。
