Alpha-Synuclein Transfers from Neurons to Oligodendrocytes
Alpha-Synuclein Transfers from Neurons to Oligodendrocytes
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DOI：
10.1002/glia.22611
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发表时间：
2014-03-01
期刊：
影响因子：
6.2
通讯作者：
Angot, Elodie
中科院分区：
文献类型：
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作者：
Reyes, Juan F.;Rey, Nolwen L.;Angot, Elodie
在多系统萎缩症(MSA)的少突胶质细胞中发现的-突触核蛋白(-syn)阳性的胶质胞浆内包涵体的来源是个谜，因为少突胶质细胞不表达-syn mRNA。最近，神经元到神经元转移的-syn被认为与帕金森病的发病有关。在这项研究中，我们探索是否可能发生类似的-syn从神经元到少突胶质细胞的转移，这可能可以解释胶质细胞质内含物是如何形成的。我们在体外和体内研究了少突胶质细胞，并检测了它们吸收不同SYN组装的能力。首先，我们用单体、寡聚和纤维状形式的-syn蛋白处理少突胶质细胞，并研究-syn摄取是否依赖于动力蛋白。其次，我们将相同的SYN物种注射到小鼠的大脑皮质中，以评估它们在体内的摄取。最后，我们监测了移植到宿主纹状体的大鼠少突胶质细胞中人-SYN的存在，显示了腺相关病毒介导的人-SYN在黑质-纹状体通路中的过表达。在这里，我们表明，少突胶质细胞在体外以浓度和时间依赖的方式摄取重组同源单体、低聚物和纤维，这一过程被DATORE抑制。此外，在我们的注射模型中，我们证明了在体内，少突胶质细胞也内化了-SYN。最后，我们提供了第一个直接证据，证明-syn可以从宿主大鼠高表达人-syn的脑神经元转移到移植的少突胶质细胞。我们的发现支持-syn从神经元到少突胶质细胞转移的假说，这一机制可能在MSA的进展和发病机制中发挥关键作用。Glia 2014；62：387-398
The origin of -synuclein (-syn)-positive glial cytoplasmic inclusions found in oligodendrocytes in multiple system atrophy (MSA) is enigmatic, given the fact that oligodendrocytes do not express -syn mRNA. Recently, neuron-to-neuron transfer of -syn was suggested to contribute to the pathogenesis of Parkinson's disease. In this study, we explored whether a similar transfer of -syn might occur from neurons to oligodendrocytes, which conceivably could explain how glial cytoplasmic inclusions are formed. We studied oligodendrocytes in vitro and in vivo and examined their ability to take up different -syn assemblies. First, we treated oligodendrocytes with monomeric, oligomeric, and fibrillar forms of -syn proteins and investigated whether -syn uptake is dynamin-dependent. Second, we injected the same -syn species into the mouse cortex to assess their uptake in vivo. Finally, we monitored the presence of human -syn within rat oligodendroglial cells grafted in the striatum of hosts displaying Adeno-Associated Virus-mediated overexpression of human -syn in the nigro-striatal pathway. Here, we show that oligodendrocytes take up recombinant -syn monomers, oligomers and, to a lesser extent, fibrils in vitro in a concentration and time-dependent manner, and that this process is inhibited by dynasore. Further, we demonstrate in our injection model that oligodendrocytes also internalize -syn in vivo. Finally, we provide the first direct evidence that -syn can transfer to grafted oligodendroglial cells from host rat brain neurons overexpressing human -syn. Our findings support the hypothesis of a neuron-to-oligodendrocyte transfer of -syn, a mechanism that may play a crucial role in the progression and pathogenesis of MSA. GLIA 2014;62:387-398