Accumulation of toxic α-synuclein oligomer within endoplasmic reticulum occurs in α-synucleinopathy in vivo.
Accumulation of toxic α-synuclein oligomer within endoplasmic reticulum occurs in α-synucleinopathy in vivo.
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DOI：
10.1523/jneurosci.5368-11.2012
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发表时间：
2012-03-07
期刊：
影响因子：
--
通讯作者：
Lee MK
中科院分区：
文献类型：
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作者：
Colla E;Jensen PH;Pletnikova O;Troncoso JC;Glabe C;Lee MK
在帕金森病（PD）和其他α-突触核蛋白病中，纤维前α-突触核蛋白（αS）寡聚物参与了其发病机制。然而，在体外系统中观察到的毒性αS低聚物在体内通常不会出现相关的α-突触核蛋白病。因此，αS低聚物对αS神经毒性的病理意义尚不清楚。本研究表明，αS在内质网/微粒体（ER/M）内积累形成α-突触核蛋白病小鼠和人脑的毒性低聚物。在α-突触核蛋白病小鼠模型中，αS低聚物最初在发病前形成，并随着疾病的进展不断积累。值得注意的是，用Salubrinal治疗αS转基因小鼠，Salubrinal是一种抗内质网应激化合物，可以延缓疾病的发生，减少αS低聚物的内质网积累。这些结果表明，具有毒性构象的αS低聚物在内质网中积累，αS低聚物依赖内质网应激与PD的病理相关性。
In Parkinson’s disease (PD) and other α-synucleinopathies, pre-fibrillar α-synuclein (αS) oligomer is implicated in the pathogenesis. However, toxic αS oligomers observed using in vitro systems are not generally seen associated α-synucleinopathy in vivo. Thus, pathologic significance of αS oligomers to αS neurotoxicity is unknown. Herein, we show that, αS that accumulate within endoplasmic reticulum/microsome(ER/M) forms toxic oligomers in mouse and human brain with the α-synucleinopathy. In the mouse model of α-synucleinopathy, αS oligomers initially form prior to the onset of disease and continue to accumulate with the disease progression. Significantly, treatment of αS transgenic mice with Salubrinal, an anti-ER stress compound that delays the onset of disease, reduces ER accumulation of αS oligomers. These results indicate that αS oligomers with toxic conformation accumulate in ER and αS oligomer dependent the ER-stress is pathologically relevant for PD.