Department of Pathology and Laboratory Medicine, 3630 Hamilton Walk, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Acta Neuropathol Commun. 2013 Jul 6;1:31. doi: 10.1186/2051-5960-1-31.
Progressive supranuclear palsy (PSP) is a neurodegenerative disorder pathologically characterized by intracellular tangles of hyperphosphorylated tau protein distributed throughout the neocortex, basal ganglia, and brainstem. A genome-wide association study identified EIF2AK3 as a risk factor for PSP. EIF2AK3 encodes PERK, part of the endoplasmic reticulum's (ER) unfolded protein response (UPR). PERK is an ER membrane protein that senses unfolded protein accumulation within the ER lumen. Recently, several groups noted UPR activation in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis, multiple system atrophy, and in the hippocampus and substantia nigra of PSP subjects. Here, we evaluate UPR PERK activation in the pons, medulla, midbrain, hippocampus, frontal cortex and cerebellum in subjects with PSP, AD, and in normal controls.
We found UPR activation primarily in disease-affected brain regions in both disorders. In PSP, the UPR was primarily activated in the pons and medulla and to a much lesser extent in the hippocampus. In AD, the UPR was extensively activated in the hippocampus. We also observed UPR activation in the hippocampus of some elderly normal controls, severity of which positively correlated with both age and tau pathology but not with Aβ plaque burden. Finally, we evaluated EIF2AK3 coding variants that influence PERK activation. We show that a haplotype associated with increased PERK activation is genetically associated with increased PSP risk.
The UPR is activated in disease affected regions in PSP and the genetic evidence shows that this activation increases risk for PSP and is not a protective response.
进行性核上性麻痹（PSP）是一种神经退行性疾病，其病理学特征为细胞内过度磷酸化的 tau 蛋白缠结分布于新皮质、基底节和脑干。全基因组关联研究确定 EIF2AK3 是 PSP 的风险因素。EIF2AK3 编码 PERK，内质网（ER）未折叠蛋白反应（UPR）的一部分。PERK 是 ER 膜蛋白，可感知 ER 腔中未折叠蛋白的积累。最近，有几个研究小组在阿尔茨海默病（AD）、帕金森病（PD）、肌萎缩侧索硬化症、多系统萎缩症以及 PSP 患者的海马体和黑质中观察到 UPR 激活。在这里，我们评估了 PSP、AD 患者和正常对照者的桥脑、延髓、中脑、海马体、额叶皮质和小脑中的 UPR PERK 激活情况。
我们发现两种疾病的病变部位均存在 UPR 激活。在 PSP 中，UPR 主要在桥脑和延髓中激活，在海马体中激活程度较低。在 AD 中，UPR 在海马体中广泛激活。我们还观察到一些老年正常对照者的海马体存在 UPR 激活，其严重程度与年龄和 tau 病理学呈正相关，但与 Aβ 斑块负担无关。最后，我们评估了影响 PERK 激活的 EIF2AK3 编码变异。我们表明，与 PERK 激活增加相关的单倍型与 PSP 风险增加相关。
UPR 在 PSP 的病变部位激活，遗传证据表明这种激活增加了 PSP 的风险，而不是一种保护反应。
