The homocysteine-inducible endoplasmic reticulum (ER) stress protein Herp counteracts mutant -synuclein-induced ER stress via the homeostatic regulation of ER-resident calcium release channel proteins
The homocysteine-inducible endoplasmic reticulum (ER) stress protein Herp counteracts mutant -synuclein-induced ER stress via the homeostatic regulation of ER-resident calcium release channel proteins
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DOI：
10.1093/hmg/ddr502
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发表时间：
2012-03-01
影响因子：
3.5
通讯作者：
Chan, Sic L.
中科院分区：
文献类型：
--
作者：
Belal, Cherine;Ameli, Neema J.;Chan, Sic L.
内质网（ER）应激是神经退行性疾病的一个启动因子或促发因子。导致ER应激的机制以及ER应激导致退行性级联反应的机制仍不清楚，但对它们的理解对于设计有效的治疗方法至关重要。在这里，我们表明，敲低Herp（同型半胱氨酸诱导的ER应激蛋白），一种具有泛素样（UBL）结构域的ER应激诱导蛋白，可使突变型突触核蛋白（Syn）诱导的ER应激介导的细胞死亡增加，突变型突触核蛋白（Syn）可导致遗传性帕金森病（PD）。在功能上，Herp通过促进蛋白酶体介导的ER驻留Ca-2释放通道的降解在维持ER稳态中发挥作用。UBL结构域的缺失或蛋白酶体的药理学抑制消除了ER Ca-2稳态的Herp介导的稳定。此外，ER Ca-2释放通道的敲低或药理学抑制改善ER应激，表明Ca-2通道的稳态调节受损促进了延长的ER应激，从而激活了ER应激相关的凋亡途径。有趣的是，在转基因突变A53 T-Syn小鼠中检测到ER应激标志物的持续上调和ER Ca-2释放通道的异常积累。总的来说，这些数据建立了受损的ER Ca-2稳态和慢性ER应激之间的因果关系，在变性级联突变体Syn诱导的，并表明，疱疹病毒是必不可少的ER应激的决议，通过维持ER Ca-2稳态。我们的研究结果表明，在PD的治疗潜力的药物，增加疱疹病毒水平或其ER Ca-2稳定作用。
Endoplasmic reticulum (ER) stress has been implicated as an initiator or contributing factor in neurodegenerative diseases. The mechanisms that lead to ER stress and whereby ER stress contributes to the degenerative cascades remain unclear but their understanding is critical to devising effective therapies. Here we show that knockdown of Herp (Homocysteine-inducible ER stress protein), an ER stress-inducible protein with an ubiquitin-like (UBL) domain, aggravates ER stress-mediated cell death induced by mutant -synuclein (Syn) that causes an inherited form of Parkinsons disease (PD). Functionally, Herp plays a role in maintaining ER homeostasis by facilitating proteasome-mediated degradation of ER-resident Ca-2 release channels. Deletion of the UBL domain or pharmacological inhibition of proteasomes abolishes the Herp-mediated stabilization of ER Ca-2 homeostasis. Furthermore, knockdown or pharmacological inhibition of ER Ca-2 release channels ameliorates ER stress, suggesting that impaired homeostatic regulation of Ca-2 channels promotes a protracted ER stress with the consequent activation of ER stress-associated apoptotic pathways. Interestingly, sustained upregulation of ER stress markers and aberrant accumulation of ER Ca-2 release channels were detected in transgenic mutant A53T-Syn mice. Collectively, these data establish a causative link between impaired ER Ca-2 homeostasis and chronic ER stress in the degenerative cascades induced by mutant Syn and suggest that Herp is essential for the resolution of ER stress through maintenance of ER Ca-2 homeostasis. Our findings suggest a therapeutic potential in PD for agents that increase Herp levels or its ER Ca-2-stabilizing action.