Elevated alpha-synuclein impairs innate immune cell function and provides a potential peripheral biomarker for Parkinson's disease.
Elevated alpha-synuclein impairs innate immune cell function and provides a potential peripheral biomarker for Parkinson's disease.
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DOI：
10.1371/journal.pone.0071634
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Johnston JA
中科院分区：
文献类型：
--
作者：
Gardai SJ;Mao W;Schüle B;Babcock M;Schoebel S;Lorenzana C;Alexander J;Kim S;Glick H;Hilton K;Fitzgerald JK;Buttini M;Chiou SS;McConlogue L;Anderson JP;Schenk DB;Bard F;Langston JW;Yednock T;Johnston JA
α-突触核蛋白与帕金森病的发病机制密切相关。由于遗传增殖或点突变导致的α-突触核蛋白表达增加导致早发性疾病。虽然已知α-突触核蛋白调节膜囊泡动力学，但尚不清楚该活性是否参与致病过程，或者体内是否存在α-突触核蛋白过度表达或突变的可测量生理效应。从BAC α-突触核蛋白转基因小鼠中分离的大胶质细胞和小胶质细胞在其自身启动子的调节下过表达α-突触核蛋白，表达α-突触核蛋白并表现出受损的细胞因子释放和吞噬作用。这些过程在体内也受到影响，无论是在腹腔巨噬细胞和小胶质细胞在中枢神经系统。将这些发现扩展到人类，我们发现与年龄匹配的对照相比，从特发性或家族性帕金森病患者中分离的单核细胞和成纤维细胞的结果相似。总之，本文提供了1）一种新的测量α-突触核蛋白功能障碍的动物模型; 2）一种测量α-突触核蛋白的同步动员及其功能相互作用的细胞系统; 3）关于先天免疫细胞功能在帕金森病和其他人类突触核蛋白病的发展和进展中的潜在作用的观察; 4）推定的外周生物标志物，以研究和追踪人类受试者中的这些过程。虽然神经元功能改变是PD的主要问题，但其他细胞类型（包括免疫细胞）中异常α-突触核蛋白表达的广泛后果可能在PD和其他突触核蛋白病的神经退行性进展中发挥重要作用。此外，增加的α-突触核蛋白和改变的吞噬作用可能为人类PD提供有用的生物标志物。
Alpha-synuclein protein is strongly implicated in the pathogenesis Parkinson's disease. Increased expression of α-synuclein due to genetic multiplication or point mutations leads to early onset disease. While α-synuclein is known to modulate membrane vesicle dynamics, it is not clear if this activity is involved in the pathogenic process or if measurable physiological effects of α-synuclein over-expression or mutation exist in vivo. Macrophages and microglia isolated from BAC α-synuclein transgenic mice, which overexpress α-synuclein under regulation of its own promoter, express α-synuclein and exhibit impaired cytokine release and phagocytosis. These processes were affected in vivo as well, both in peritoneal macrophages and microglia in the CNS. Extending these findings to humans, we found similar results with monocytes and fibroblasts isolated from idiopathic or familial Parkinson's disease patients compared to age-matched controls. In summary, this paper provides 1) a new animal model to measure α-synuclein dysfunction; 2) a cellular system to measure synchronized mobilization of α-synuclein and its functional interactions; 3) observations regarding a potential role for innate immune cell function in the development and progression of Parkinson's disease and other human synucleinopathies; 4) putative peripheral biomarkers to study and track these processes in human subjects. While altered neuronal function is a primary issue in PD, the widespread consequence of abnormal α-synuclein expression in other cell types, including immune cells, could play an important role in the neurodegenerative progression of PD and other synucleinopathies. Moreover, increased α-synuclein and altered phagocytosis may provide a useful biomarker for human PD.
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影响因子：
7.7
作者：
Darios, Frederic;Ruiperez, Violeta;Davletov, Bazbek
通讯作者：
Davletov, Bazbek
DOI：
10.1083/jcb.201004096
发表时间：
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期刊：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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