Chromosome 22q11.2 deletion causes PERK-dependent vulnerability in dopaminergic neurons.
Chromosome 22q11.2 deletion causes PERK-dependent vulnerability in dopaminergic neurons.
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DOI：
10.1016/j.ebiom.2020.103138
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发表时间：
2021-01
期刊：
影响因子：
11.1
通讯作者：
Ozaki N
中科院分区：
文献类型：
--
作者：
Arioka Y;Shishido E;Kushima I;Suzuki T;Saito R;Aiba A;Mori D;Ozaki N
染色体22q11.2缺失是多种神经精神疾病的极高风险遗传因素；然而，与22q11.2缺失相关的人类脑病理在细胞和分子水平上仍不清楚。我们从健康对照组(对照组)和22q11.2缺失患者(22DS组)获得iPS细胞，并将其分化为多巴胺能神经元。用半定量蛋白质组学分析比较两组间的差异。接下来，我们进行了分子、细胞生物学和药理学检测。半定量的蛋白质组学分析发现，在22DS组中，内质网(ER)中的蛋白质加工是变化最大的途径。特别是，我们发现22DS组蛋白激酶R样内质网激酶(PERK)的表达和活性存在严重缺陷。在22q11.2缺失小鼠模型的中脑中，也显示出PERK表达的降低。22DS组表现出特征性的表型，包括对内质网应激的耐受性差，F-肌动蛋白动力学异常，蛋白质合成减少。PERK活性的药理学操作挽救了一些表型，并在PERK缺乏的多巴胺能神经元中出现表型。最后，我们发现DGCR14与PERK表达的减少有关。我们的发现使我们得出结论，22q11.2缺失导致多巴胺能神经元的各种脆弱性，依赖于PERK功能障碍。这项研究得到了赠款编号JP20dm0107087、JP20dm0207075、JP20ak0101113、JP20dk0307081和JP18dm0207004h0005的资助；16K19760、19K08015、18H04040和18K19511；在资助金编号201810122；以及2019年iPS日本学院资助金。
The chromosome 22q11.2 deletion is an extremely high risk genetic factor for various neuropsychiatric disorders; however, the 22q11.2 deletion-related brain pathology in humans at the cellular and molecular levels remains unclear. We generated iPS cells from healthy controls (control group) and patients with 22q11.2 deletion (22DS group), and differentiated them into dopaminergic neurons. Semiquantitative proteomic analysis was performed to compare the two groups. Next, we conducted molecular, cell biological and pharmacological assays. Semiquantitative proteomic analysis identified ‘protein processing in the endoplasmic reticulum (ER)’ as the most altered pathway in the 22DS group. In particular, we found a severe defect in protein kinase R-like endoplasmic reticulum kinase (PERK) expression and its activity in the 22DS group. The decreased PERK expression was also shown in the midbrain of a 22q11.2 deletion mouse model. The 22DS group showed characteristic phenotypes, including poor tolerance to ER stress, abnormal F-actin dynamics, and decrease in protein synthesis. Some of phenotypes were rescued by the pharmacological manipulation of PERK activity and phenocopied in PERK-deficient dopaminergic neurons. We lastly showed that DGCR14 was associated with reduction in PERK expression. Our findings led us to conclude that the 22q11.2 deletion causes various vulnerabilities in dopaminergic neurons, dependent on PERK dysfunction. This study was supported by the under grant nos JP20dm0107087, JP20dm0207075, JP20ak0101113, JP20dk0307081, and JP18dm0207004h0005; the under grant nos. 16K19760, 19K08015, 18H04040, and 18K19511; the under grant no. 201810122; and 2019 iPS Academia Japan Grant.
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影响因子：
6.8
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