Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Kyoto, Japan.
Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Sakyo-ku, Kyoto, Japan.
Biochem Biophys Res Commun. 2018 Nov 30;506(3):516-521. doi: 10.1016/j.bbrc.2018.10.094. Epub 2018 Oct 22.
Endoplasmic reticulum (ER) stress may play a role in the etiology of Parkinson's disease (PD). We have previously reported that ubiquitin ligase 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase degradation 1 (HRD1) involved in ER stress degrades unfolded protein that accumulates in the ER due to loss of function of Parkin, which is a causative factor in familial PD. We have also demonstrated that cell death is suppressed by the degradation of unfolded proteins. These findings indicate that HRD1 may serve as a compensatory mechanism for the loss of function of Parkin in familial PD patients. However, the role of HRD1 in sporadic PD has not yet been identified. This study aimed to reveal the roles of HRD1 and associated molecules in a cellular model of PD. We demonstrated that expressions of HRD1 and Suppressor/Enhancer Lin12 1-like (SEL1L: a HRD1 stabilizer) increased in SH-SY5Y human neuroblastoma cells upon exposure to 6-hydroxydopamine (6-OHDA). The 6-OHDA-induced cell death was suppressed in cells overexpressing wt-HRD1, whereas cell death was enhanced in cells with knockdown of HRD1 expression. These results suggest that HRD1 is a key molecule involved in 6-OHDA-induced cell death. By contrast, suppression of SEL1L expression decreased the amount of HRD1 protein. As a result, 6-OHDA-induced cell death was enhanced in cells suppressing SEL1L expression, and this cell death was much more evident than that in cells with suppression of HRD1 expression. These findings strongly indicate that SEL1L is necessary for maintaining and stabilizing the amount of HRD1 protein, and stabilizing the amount of HRD1 protein through SEL1L may serve to protect against 6-OHDA-induced cell death. Furthermore, the expression of Parkin was reinforced when HRD1 mRNA had been suppressed in cells, but was not observed when SEL1L mRNA had been restrained. It is possible that Parkin expression is induced as a compensatory mechanism when HRD1 mRNA decreases. This intracellular transduction may suppress the enhancement of 6-OHDA-induced cell death caused by the loss of HRD1. Taken together with these results, it is suggested that HRD1 and its stabilizer (SEL1L) are key molecules for elucidating the pathogenesis and treatment of PD.
内质网（ER）应激可能在帕金森病（PD）的发病机制中起作用。我们之前报道过，参与 ER 应激的泛素连接酶 3-羟基-3-甲基戊二酰辅酶 A（HMG-CoA）还原酶降解 1（HRD1）降解由于 Parkin 功能丧失而在 ER 中积累的未折叠蛋白，Parkin 是家族性 PD 的致病因素。我们还证明，细胞死亡可以通过未折叠蛋白的降解来抑制。这些发现表明，HRD1 可能是家族性 PD 患者 Parkin 功能丧失的补偿机制。然而，HRD1 在散发性 PD 中的作用尚未确定。本研究旨在揭示 HRD1 及其相关分子在 PD 细胞模型中的作用。我们证明，在暴露于 6-羟多巴胺（6-OHDA）后，SH-SY5Y 人神经母细胞瘤细胞中 HRD1 和 Suppressor/Enhancer Lin12 1-like（SEL1L：HRD1 稳定剂）的表达增加。在过表达 wt-HRD1 的细胞中，6-OHDA 诱导的细胞死亡受到抑制，而在 HRD1 表达下调的细胞中，细胞死亡增强。这些结果表明 HRD1 是参与 6-OHDA 诱导的细胞死亡的关键分子。相比之下，抑制 SEL1L 表达会减少 HRD1 蛋白的含量。因此，在抑制 SEL1L 表达的细胞中，6-OHDA 诱导的细胞死亡增强，并且这种细胞死亡比抑制 HRD1 表达的细胞中的细胞死亡更为明显。这些发现强烈表明，SEL1L 是维持和稳定 HRD1 蛋白含量所必需的，并且通过 SEL1L 稳定 HRD1 蛋白含量可能有助于防止 6-OHDA 诱导的细胞死亡。此外，当细胞中 HRD1 mRNA 被抑制时，Parkin 的表达增强，但当 SEL1L mRNA 受到抑制时，Parkin 的表达没有观察到。当 HRD1 mRNA 减少时，Parkin 的表达可能被诱导作为一种补偿机制。这种细胞内转导可能抑制 HRD1 丧失引起的 6-OHDA 诱导的细胞死亡增强。综合这些结果表明，HRD1 和其稳定剂（SEL1L）是阐明 PD 发病机制和治疗方法的关键分子。
