Circumstantial evidence points to a pathological role of alpha-synuclein (aSyn; gene symbol SNCA), conferred by aSyn misfolding and aggregation, in Parkinson disease (PD) and related synucleinopathies. Several findings in experimental models implicate perturbations in the tissue homeostatic mechanisms triggered by pathological aSyn accumulation, including impaired redox homeostasis, as significant contributors in the pathogenesis of PD. The nuclear factor erythroid 2-related factor (NRF2/Nrf2) is recognized as ‘the master regulator of cellular anti-oxidant response’, both under physiological as well as in pathological conditions. Using immunohistochemical analyses, we show a robust nuclear NRF2 accumulation in post-mortem PD midbrain, detected by NRF2 phosphorylation on the serine residue 40 (nuclear active p-NRF2, S40). Curated gene expression analyses of four independent publicly available microarray datasets revealed considerable alterations in NRF2-responsive genes in the disease affected regions in PD, including substantia nigra, dorsal motor nucleus of vagus, locus coeruleus and globus pallidus. To further examine the putative role of pathological aSyn accumulation on nuclear NRF2 response, we employed a transgenic mouse model of synucleionopathy (M83 line, expressing the mutant human A53T aSyn), which manifests widespread aSyn pathology (phosphorylated aSyn; S129) in the nervous system following intramuscular inoculation of exogenous fibrillar aSyn. We observed strong immunodetection of nuclear NRF2 in neuronal populations harboring p-aSyn (S129), and found an aberrant anti-oxidant and inflammatory gene response in the affected neuraxis. Taken together, our data support the notion that pathological aSyn accumulation impairs the redox homeostasis in nervous system, and boosting neuronal anti-oxidant response is potentially a promising approach to mitigate neurodegeneration in PD and related diseases.

中文翻译：

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帕金森病中的α-突触核蛋白病理激活稳态 NRF2 抗氧化反应

间接证据表明，α-突触核蛋白（aSyn；基因符号 SNCA）在帕金森病 (PD) 和相关突触核蛋白病中的病理作用由 aSyn 错误折叠和聚集赋予。实验模型中的一些发现表明，病理性 aSyn 积累引发的组织稳态机制的扰动，包括氧化还原稳态受损，是 PD 发病机制的重要因素。核因子红细胞 2 相关因子 (NRF2/Nrf2) 被认为是“细胞抗氧化反应的主要调节因子”，无论是在生理条件下还是在病理条件下。使用免疫组织化学分析，我们通过丝氨酸残基 40（核活性 p-NRF2，S40）上的 NRF2 磷酸化检测到死后 PD 中脑中的强大核 NRF2 积累。对四个独立的公开可用微阵列数据集的精选基因表达分析揭示了 PD 疾病影响区域中 NRF2 响应基因的显着改变，包括黑质、迷走神经背运动核、蓝斑和苍白球。为了进一步检查病理性 aSyn 积累对核 NRF2 反应的推定作用，我们采用了突触核蛋白病的转基因小鼠模型（M83 系，表达突变的人类 A53T aSyn），其在神经系统中表现出广泛的 aSyn 病理（磷酸化 aSyn；S129）肌内接种外源性原纤维 aSyn 后。我们在含有 p-aSyn (S129) 的神经元群体中观察到核 NRF2 的强免疫检测，并在受影响的神经轴中发现了异常的抗氧化和炎症基因反应。综合起来，