Neuronal PAD4 expression and protein citrullination: Possible role in production of autoantibodies associated with neurodegenerative disease
Neuronal PAD4 expression and protein citrullination: Possible role in production of autoantibodies associated with neurodegenerative disease
复制标题
DOI：
10.1016/j.jaut.2012.03.004
复制
发表时间：
2012-06-01
影响因子：
12.8
通讯作者：
Nagele, Robert G.
中科院分区：
文献类型：
--
作者：
Acharya, Nimish K.;Nagele, Eric P.;Nagele, Robert G.
肽基精氨酸脱亚胺酶（PAD）催化称为瓜氨酸的翻译后蛋白质修饰反应，其中精氨酸转化为瓜氨酸。这种修饰与包括类风湿性关节炎（RA）在内的自身免疫性疾病的发病机制有关。最近，一些研究表明，阿尔茨海默病（AD），一种破坏性的神经退行性疾病，可能有自身免疫成分。在本研究中，我们研究了PAD和瓜氨酸蛋白的表达在脑反应性自身抗体的产生中发挥作用的可能性，这些抗体可能有助于阿尔茨海默病相关的脑病理学。在这里，我们报告的选择性表达的PAD亚型，PAD 2和PAD 4，分别在星形胶质细胞和神经元，和伴随的积累的瓜氨酸蛋白的PAD 4表达细胞，包括海马和大脑皮层的神经元。PAD和瓜氨酸化蛋白的表达在参与AD病理学典型神经退行性变化的脑区域中是突出的。此外，我们还证明了五肽重复结构域2（PTCD2）蛋白，一个突出的AD诊断自身抗体的抗原靶点，是目前在AD大脑中的瓜氨酸化形式。我们的研究结果表明，疾病相关的神经元损失导致细胞内容物的释放，包括瓜氨酸化蛋白，进入脑垂体。我们认为这些瓜氨酸化蛋白及其降解片段进入血液和淋巴循环，其中一些能够引发免疫反应，导致自身抗体的产生。AD和其他神经退行性疾病的长期和进行性导致免疫系统长期暴露于这些瓜氨酸化产物，并可能导致自身抗体的持续产生。(C)2012爱思唯尔有限公司保留所有权利。
Peptidyl arginine deiminases (PADs) catalyze a post-translational protein modification reaction called citrullination, where arginine is converted to citrulline. This modification has been linked to the pathogenesis of autoimmune diseases including rheumatoid arthritis (RA). More recently, several studies have suggested that Alzheimer's disease (AD), a devastating neurodegenerative disorder, may have an autoimmune component. In the present study, we have investigated the possibility that expression of PADs and protein citrullination plays a role in the production of brain-reactive autoantibodies that may contribute to Alzheimer's-related brain pathology. Here, we report the selective expression of the PAD isoforms, PAD2 and PAD4, in astrocytes and neurons, respectively, and the concomitant accumulation of citrullinated proteins within PAD4-expressing cells, including neurons of the hippocampus and cerebral cortex. Expression of PADs and citrullinated proteins is prominent in brain regions engaged in neurodegenerative changes typical for AD pathology. Furthermore, we also demonstrate that the pentatricopeptide repeat domain2 (PTCD2) protein, an antigen target of a prominent AD diagnostic autoantibody, is present in a citrullinated form in AD brains. Our results suggest that disease-associated neuronal loss results in the release of cellular contents, including citrullinated proteins, into the brain interstitium. We propose that these citrullinated proteins and their degradation fragments enter into the blood and lymphatic circulation, and some are capable of eliciting an immune response that results in the production of autoantibodies. The long-term and progressive nature of AD and other neurodegenerative diseases results in chronic exposure of the immune system to these citrullinated products and may drive the continual production of autoantibodies. (C) 2012 Elsevier Ltd. All rights reserved.