Endoplasmic reticulum stress is important for the manifestations of α-synucleinopathy in vivo.
Endoplasmic reticulum stress is important for the manifestations of α-synucleinopathy in vivo.
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DOI：
10.1523/jneurosci.5367-11.2012
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发表时间：
2012-03-07
期刊：
影响因子：
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通讯作者：
Lee MK
中科院分区：
文献类型：
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作者：
Colla E;Coune P;Liu Y;Pletnikova O;Troncoso JC;Iwatsubo T;Schneider BL;Lee MK
错误折叠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变性有机制联系。然而，αS如何引起神经退行性变尚不清楚。由于错误折叠蛋白的细胞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-突触核蛋白病的神经退行性变。利用A53T突变型人αS转基因（A53TαS Tg）小鼠α-突触核蛋白病模型，我们发现αS Tg模型的发病与ER伴侣蛋白在表现αS病理的神经元中的诱导一致。然而，神经元ER伴侣诱导不伴有磷酸化- eif2 α的激活，表明α-突触核蛋白病与UPR异常相关，可促进细胞死亡。ERS/UPR的诱导与ER/微粒体（ER/M）相关αS单体和聚集体水平升高有关。值得注意的是，人类PD患者的ER/M αS的相对水平也高于对照组。此外，αS与内质网伴侣相互作用，αS的过表达使神经元细胞对内质网诱导的毒性敏感，提示αS可能直接影响内质网功能。这一观点得到了内质网激活的caspase-12和内质网相关多泛素积累的支持。更重要的是，抗ers化合物Salubrinal治疗可显著减轻A53Tα s-依赖性多巴胺能神经变性小鼠模型和腺相关病毒转导的A53Tα s-依赖性多巴胺能神经变性模型的疾病表现。我们的数据表明，内质网内αS的积累导致内质网慢性应激状态，从而导致α-突触核蛋白病的神经退行性变。减轻慢性ERS可能是治疗PD和其他α-突触核蛋白病的有效方法。
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 chaperone 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 A53T α S-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.