Early Neurodegeneration in the Brain of a Child Without Functional PKR-like Endoplasmic Reticulum Kinase
Early Neurodegeneration in the Brain of a Child Without Functional PKR-like Endoplasmic Reticulum Kinase
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DOI：
10.1097/nen.0000000000000224
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发表时间：
2015-08-01
影响因子：
3.2
通讯作者：
Hoeglinger, Guenter U.
中科院分区：
文献类型：
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作者：
Bruch, Julius;Kurz, Carolin;Hoeglinger, Guenter U.
我们首次详细检查了一例沃尔科特-雷里森综合征患者的大脑。Wolcott-Rallison综合征是一种极其罕见的临床表现，由PERK基因EIF2AK3突变导致蛋白激酶R样内质网状激酶(PERK)功能缺失。蛋白激酶R样内质网激酶被认为在几种神经退行性疾病中起着重要的致病作用，包括阿尔茨海默病、其他神经官能症和帕金森病。一名4岁7个月大的男性患者的大脑显示出病理和免疫组织化学证据，表明几年来没有PERK足以引起让人联想到各种神经退行性疾病的早期变化。这些包括神经原纤维缠结(如进行性核上性麻痹)，FUS免疫阳性神经元和p62免疫阳性神经元，以及反应性胶质细胞变化。我们还检测到Lc3和泛素的p62阳性斑点共同免疫染色的数量增加，表明自噬通量发生了变化。研究缺乏PERK功能的人脑提供了一个机会，在活人体内存在所有正常活跃的补偿机制的情况下，评估PERK不起作用的长期后果，从而证实PERK对于大脑中的自噬和神经退化的重要性。
We report the first detailed examination of the brain of a patient with Wolcott-Rallison syndrome. Wolcott-Rallison syndrome is an extremely rare clinical manifestation of a lack of protein kinase R-like endoplasmic reticulum kinase (PERK) function caused by mutations in the PERK gene EIF2AK3. Protein kinase R-like endoplasmic reticulum kinase is thought to play a significant pathogenetic role in several neurodegenerative diseases, including Alzheimer disease, other tauopathies, and Parkinson disease. The brain of a male patient aged 4 years 7 months showed pathologic and immunohistochemical evidence that the absence of PERK for several years is sufficient to induce early changes reminiscent of various neurodegenerative conditions. These include neurofibrillary tangles (as in progressive supranuclear palsy), FUS-immunopositive and p62-immunopositive neurons, and reactive glial changes. We also detected an increased amount of p62-positive puncta coimmunostaining for LC3 and ubiquitin, suggesting changes in autophagic flux. Studying a human brain with absent PERK function presents the opportunity to assess the long-term consequences of nonfunctioning of PERK in the presence of all of the compensatory mechanisms that are normally active in a living human, thereby confirming the importance of PERK for autophagy in the brain and for neurodegeneration.