Baek Jean-Ha, Mamula Dejan, Tingstam Beata, Pereira Marcela, He Yachao, Svenningsson Per
Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
Front Neurosci. 2019 Jul 5;13:697. doi: 10.3389/fnins.2019.00697. eCollection 2019.
Accumulation of misfolded proteins results in cellular stress, and is detected by specific sensors in the endoplasmic reticulum, collectively known as the unfolded protein response (UPR). It has been prominently proposed that the UPR is involved in the pathophysiology of Parkinson's disease (PD). In the present study, the levels of the UPR proteins and mRNA transcripts were quantified in brain tissue from PD patients and matched controls. The level of a key mediator of the UPR pathway, glucose-regulated protein 78 (GRP78), was significantly decreased in temporal cortex and cingulate gyrus, whereas there were no significant changes in the caudate nucleus, prefrontal, or parietal cortex regions. On the other hand, GRP78 mRNA level was significantly increased in caudate nucleus, cingulate gyrus, prefrontal, and parietal cortex regions. GRP78 protein level was also measured in plasma and cerebrospinal fluid, but there were no differences in these levels between PD patients and control subjects. Furthermore, immunofluorescence labeling of the CD4 T cells from PD patients showed that GRP78 protein is found in the cytoplasm. However, GRP78 level in PD patients was not significantly different from control subjects. Unlike the previous Lewy body dementia study, the present investigation reports reduced cortical protein, but increased transcript levels of GPR78 in PD. In summary, these data provide further evidence that GRP78 regulation is dysfunctional in the brains of PD patients.
错误折叠蛋白的积累会导致细胞应激，并被内质网中的特定传感器检测到，这些传感器统称为未折叠蛋白反应（UPR）。有观点明确提出，UPR参与帕金森病（PD）的病理生理过程。在本研究中，对PD患者和配对对照的脑组织中UPR蛋白和mRNA转录本水平进行了定量分析。UPR途径的关键介质葡萄糖调节蛋白78（GRP78）的水平在颞叶皮质和扣带回显著降低，而在尾状核、前额叶或顶叶皮质区域没有显著变化。另一方面，GRP78 mRNA水平在尾状核、扣带回、前额叶和顶叶皮质区域显著升高。还检测了血浆和脑脊液中的GRP78蛋白水平，但PD患者和对照受试者之间这些水平没有差异。此外，对PD患者的CD4 T细胞进行免疫荧光标记显示，GRP78蛋白存在于细胞质中。然而，PD患者的GRP78水平与对照受试者没有显著差异。与之前关于路易体痴呆的研究不同，本研究报告了PD患者皮质蛋白减少，但GPR78转录水平升高。总之，这些数据进一步证明了GRP78调节在PD患者大脑中存在功能障碍。
