Division of Pharmacology, Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy.
J Neurochem. 2011 Feb;116(4):588-605. doi: 10.1111/j.1471-4159.2010.07143.x. Epub 2011 Jan 19.
Accumulation of misfolded proteins in the endoplasmic reticulum (ER) is the main event leading to the induction of the ER stress-related unfolded protein response (UPR). Recent postmortem evaluation, showing that the UPR pathway is activated in nigral dopaminergic neurons bearing α-synuclein inclusions in the brain of Parkinson's disease (PD) patients, suggests that the activation of the UPR may be induced by the accumulation of α-synuclein. In this study, we show that the misfolded protein-sensor/UPR activator glucose-regulated protein 78/immunoglobulin heavy chain-binding protein was bound to α-synuclein and was increased in 'in vitro' and 'in vivo' models showing aggregated α-synuclein accumulation. Moreover, α-synuclein accumulation induced the expression of the UPR-related activating transcription factor 4/cAMP-responsive element-2. These findings indicate that activation of the UPR pathway in the PD brain is associated with α-synuclein accumulation occurring in part within the ER.
内质网（ER）中错误折叠蛋白的积累是导致内质网应激相关未折叠蛋白反应（UPR）诱导的主要事件。最近的尸检评估表明，在帕金森病（PD）患者大脑中携带α-突触核蛋白包涵体的黑质多巴胺能神经元中，UPR 途径被激活，这表明 UPR 的激活可能是由α-突触核蛋白的积累引起的。在这项研究中，我们表明，错误折叠蛋白传感器/UPR 激活剂葡萄糖调节蛋白 78/免疫球蛋白重链结合蛋白与α-突触核蛋白结合，并在显示聚集的α-突触核蛋白积累的“体外”和“体内”模型中增加。此外，α-突触核蛋白的积累诱导了 UPR 相关激活转录因子 4/cAMP 反应元件-2 的表达。这些发现表明，PD 大脑中 UPR 途径的激活与部分发生在 ER 内的α-突触核蛋白积累有关。
