Slodzinski H, Moran L B, Michael G J, Wang B, Novoselov S, Cheetham M E, Pearce R K B, Graeber M B
University Department of Neuropathology, Imperial College, University of London and Hammersmith Hospitals Trust, UK.
Clin Neuropathol. 2009 Sep-Oct;28(5):333-43.
Recent studies highlight the role of endoplasmic reticulum (ER) stress and aberrant protein degradation in the pathogenesis of neurodegenerative disorders. Herp which is encoded by the HERPUD 1 (homocysteine-inducible, endoplasmic reticulum stress-inducible, ubiquitin-like domain member 1) gene is a stress-response protein localized in the ER membrane of neurons and other cell types. Herp has been suggested to improve ER-folding, decrease ER protein load, and participate in ER-associated degradation (ERAD) of proteins.
Based on microarray expression profiling results we have predicted an increased expression of HERPUD1 in the substantia nigra of Parkinson's disease (PD) patients. We have now used brain tissue of some of the same and additional cases of sporadic PD to localize Herp mRNA and protein in individual cell types.
We found expression of Herp in neurons and in glial cells including astrocytes. These findings were corroborated by in situ hybridization. Accumulation of Herp protein was also detected in the core of Lewy bodies suggesting a role in their formation. Hierarchical clustering analysis identified TWINKLE (PEO1) as the gene whose expression profile was most similar to that of Herp across the PD cohort.
The nigral glial cells that expressed Herp at a high level resembled TUNEL-positive glia. While some of these cells likely undergo degeneration, the strong up-regulation of Herp in glia could help to explain the inflammation-like changes observed in PD ("neuroinflammation") as it has been shown that the unfolded protein response serves as an important regulator of inflammatory genes in other organs.
最近的研究突出了内质网（ER）应激和异常蛋白质降解在神经退行性疾病发病机制中的作用。由HERPUD 1（同型半胱氨酸诱导、内质网应激诱导、泛素样结构域成员1）基因编码的Herp是一种应激反应蛋白，定位于神经元和其他细胞类型的内质网膜。有人提出Herp可改善内质网折叠、降低内质网蛋白质负荷，并参与蛋白质的内质网相关降解（ERAD）。
基于微阵列表达谱分析结果，我们预测帕金森病（PD）患者黑质中HERPUD1表达增加。我们现在使用了一些相同的以及额外的散发性PD病例的脑组织，以在个体细胞类型中定位Herp mRNA和蛋白质。
我们发现Herp在神经元和包括星形胶质细胞在内的神经胶质细胞中表达。原位杂交证实了这些发现。在路易小体的核心也检测到Herp蛋白的积累，表明其在路易小体形成中起作用。层次聚类分析确定TWINKLE（PEO1）是在整个PD队列中表达谱与Herp最相似的基因。
高水平表达Herp的黑质神经胶质细胞类似于TUNEL阳性神经胶质细胞。虽然这些细胞中的一些可能会发生变性，但神经胶质细胞中Herp的强烈上调可能有助于解释PD中观察到的炎症样变化（“神经炎症”），因为已经表明未折叠蛋白反应是其他器官中炎症基因的重要调节因子。
