α-Synuclein (α-Syn) is a small presynaptic protein and its mutant forms (e.g. A53T) are known to be directly associated with Parkinson's disease (PD). Pathophysiological mechanisms underlying α-Syn-mediated neurodegeneration in PD still remain to be explored. However, several studies strongly support that overexpression of mutant α-Syn causes reduced release of dopamine (DA) in the brain, and contributes to motor deficits in PD. Using a favorable genetic model Drosophila larva, we examined whether reduced DA release is enough to induce key PD symptoms (i.e. locomotion deficiency and DA neurodegeneration), mimicking a PD gene α-Syn. In order to reduce DA release, we expressed electrical knockout (EKO) gene in DA neurons, which is known to make neurons hypo-excitable. EKO led to a decrease in a DA neuronal marker signal (i.e., TH - tyrosine hydroxylase) and locomotion deficits in Drosophila larva. In contrast, acute and prolonged exposure to blue light (BL, 470 nm) was sufficient to activate channelrhodopsin 2 (ChR2) and rescue PD symptoms caused by both α-Syn and EKO. We believe this is for the first time to confirm that locomotion defects by a genetic PD factor such as α-Syn can be rescued by increasing DA neuronal excitability with an optogenetic approach. Our findings strongly support that PD is a failure of DA synaptic transmission, which can be rescued by optogenetic activation of ChR2.

中文翻译：

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α-突触核蛋白和EKO基因引起的运动功能障碍和多巴胺能变性的光遗传学挽救。

α-突触核蛋白（α-Syn）是一种小的突触前蛋白，其突变形式（例如A53T）已知与帕金森氏病（PD）直接相关。PD中由α-Syn介导的神经变性的病理生理机制仍有待探索。但是，一些研究强烈支持突变体α-Syn的过度表达会导致脑中多巴胺（DA）的释放减少，并导致PD运动障碍。使用有利的果蝇遗传模型幼虫，我们检查了减少的DA释放是否足以诱发主要的PD症状（即运动不足和DA神经变性），从而模仿了PD基因α-Syn。为了减少DA的释放，我们在DA神经元中表达了电敲除（EKO）基因，已知该基因使神经元的兴奋性降低。EKO导致果蝇中DA神经元信号（即TH-酪氨酸羟化酶）的减少和运动功能障碍幼虫。相反，急性和长时间暴露于蓝光（BL，470 nm）足以激活通道视紫红质2（ChR2）并挽救由α-Syn和EKO引起的PD症状。我们认为，这是首次确认通过光遗传学方法提高DA神经元兴奋性可以挽救遗传PD因子（例如α-Syn）引起的运动缺陷。我们的发现强烈支持PD是DA突触传递的失败，可以通过ChR2的光遗传学激活来挽救PD。