Heat-shock protein 70 modulates toxic extracellular α-synuclein oligomers and rescues trans-synaptic toxicity
Heat-shock protein 70 modulates toxic extracellular α-synuclein oligomers and rescues trans-synaptic toxicity
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DOI：
10.1096/fj.10-164624
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发表时间：
2011-01-01
期刊：
影响因子：
4.8
通讯作者：
McLean, Pamela J.
中科院分区：
文献类型：
--
作者：
Danzer, Karin M.;Ruf, Wolfgang P.;McLean, Pamela J.
最近报道了帕金森病（PD）脑中幼稚移植胚胎干细胞中聚集的α-突触核蛋白（α-syn）的反常外观，突出了PD中α-syn的神经元到神经元传递的可能性。在这里，我们证明了在细胞模型的存在下，在细胞外空间的α-syn寡聚体，它们的神经元的摄取，逆行轴突运输到细胞索马，和对邻近细胞的有害影响。此外，我们证明了Hsp 70分子伴侣α-syn在细胞外空间，并减少细胞外α-syn寡聚体的形成和相关的毒性。这些新发现提供了证据，表明细胞外α syn寡聚体可能是PD病理传播的关键因素，而Hsp 70对它们的调节代表了治疗干预的潜在新靶点。Danzer，K. M.，Ruf，W. P.，Putcha，P.，Joyner，D.，桥本，T.，Glabe，C.，海曼，B。T.，姆克林，P. J. Heat-shock protein 70 modulates toxic extracellular alpha-synuclein oligomers and rescues trans-synaptic toxicity. FASEB J.25，326-336（2011）. www.fasebj.org
The paradoxical appearance of aggregated alpha-synuclein (alpha syn) in naive transplanted embryonic stem cells in Parkinson's disease (PD) brains has recently been reported, highlighting the possibility of neuron to neuron transmission of alpha syn in PD. Here, we demonstrate in a cellular model the presence of alpha syn oligomers in the extracellular space, their uptake by neurons, retrograde axonal transport to cell soma, and detrimental effects on neighboring cells. Moreover, we demonstrate that Hsp70 chaperones alpha syn in the extracellular space and reduces extracellular alpha syn oligomer formation and related toxicity. These novel findings provide evidence that extracellular alpha syn oligomers may represent a crucial player in the propagation of pathology in PD, with their modulation by Hsp70 representing a potential new target for therapeutic interventions.-Danzer, K. M., Ruf, W. P., Putcha, P., Joyner, D., Hashimoto, T., Glabe, C., Hyman, B. T., McLean, P. J. Heat-shock protein 70 modulates toxic extracellular alpha-synuclein oligomers and rescues trans-synaptic toxicity. FASEB J. 25, 326-336 (2011). www.fasebj.org