Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
J Neurosci. 2012 Mar 7;32(10):3306-20. doi: 10.1523/JNEUROSCI.5367-11.2012.
Accumulation of misfolded α-synuclein (αS) is mechanistically linked to neurodegeneration in Parkinson's disease (PD) and other α-synucleinopathies. However, how αS causes neurodegeneration is unresolved. Because cellular accumulation of misfolded proteins can lead to endoplasmic reticulum stress/unfolded protein response (ERS/UPR), chronic ERS could contribute to neurodegeneration in α-synucleinopathy. Using the A53T mutant human αS transgenic (A53TαS Tg) mouse model of α-synucleinopathy, we show that disease onset in the αS Tg model is coincident with induction of ER chaperones in neurons exhibiting αS pathology. However, the neuronal ER chaperone induction was not accompanied by the activation of phospho-eIF2α, indicating that α-synucleinopathy is associated with abnormal UPR that could promote cell death. Induction of ERS/UPR was associated with increased levels of ER/microsomal (ER/M) associated αS monomers and aggregates. Significantly, human PD cases also exhibit higher relative levels of ER/M αS than the control cases. Moreover, αS interacts with ER chaperones and overexpression of αS sensitizes neuronal cells to ERS-induced toxicity, suggesting that αS may have direct impact on ER function. This view is supported by the presence of ERS-activated caspase-12 and the accumulation of ER-associated polyubiquitin. More important, treatment with Salubrinal, an anti-ERS compound, significantly attenuates disease manifestations in both the A53TαS Tg mouse model and the adeno-associated virus-transduced rat model of A53TαS-dependent dopaminergic neurodegeneration. Our data indicate that the accumulation αS within ER leads to chronic ER stress conditions that contribute to neurodegeneration in α-synucleinopathies. Attenuating chronic ERS could be an effective therapy for PD and other α-synucleinopathies.
错误折叠的α-突触核蛋白（αS）的积累与帕金森病（PD）和其他α-突触核蛋白病的神经退行性变在机制上有关。然而，αS 如何引起神经退行性变仍未解决。由于细胞内错误折叠蛋白的积累可导致内质网应激/未折叠蛋白反应（ERS/UPR），慢性 ERS 可能导致α-突触核蛋白病中的神经退行性变。我们使用 A53T 突变型人αS 转基因（A53TαS Tg）小鼠模型的α-突触核蛋白病，表明该疾病的发病与表现出αS 病理学的神经元中内质网伴侣的诱导同时发生。然而，神经元内质网伴侣的诱导并没有伴随着磷酸化 eIF2α 的激活，这表明α-突触核蛋白病与异常 UPR 相关，这可能促进细胞死亡。ERS/UPR 的诱导与内质网/微粒体（ER/M）相关的αS 单体和聚集体水平的增加有关。重要的是，人类 PD 病例也表现出比对照病例更高的 ER/MαS 相对水平。此外，αS 与内质网伴侣相互作用，并且αS 的过表达使神经元细胞对 ERS 诱导的毒性敏感，这表明αS 可能对 ER 功能具有直接影响。这种观点得到了 ERS 激活的半胱氨酸蛋白酶-12的存在和 ER 相关多聚泛素的积累的支持。更重要的是，用 Salubrinal（一种抗 ERS 化合物）治疗可显著减轻 A53TαS Tg 小鼠模型和腺相关病毒转导的 A53TαS 依赖性多巴胺能神经退行性变大鼠模型中的疾病表现。我们的数据表明，αS 在 ER 内的积累导致慢性 ER 应激条件，这有助于α-突触核蛋白病中的神经退行性变。减轻慢性 ERS 可能是 PD 和其他α-突触核蛋白病的有效治疗方法。
