Alpha-synuclein (α-syn) aggregation into proteinaceous intraneuronal inclusions, called Lewy bodies (LBs), is the neuropathological hallmark of Parkinson’s disease (PD) and related synucleinopathies. However, the exact role of α-syn inclusions in PD pathogenesis remains elusive. This lack of knowledge is mainly due to the absence of optimal α-syn-based animal models that recapitulate the different stages of neurodegeneration. Here we describe a novel approach for a systemic delivery of viral particles carrying human α-syn allowing for a large-scale overexpression of this protein in the mouse brain. This approach is based on the use of a new generation of adeno-associated virus (AAV), AAV-PHP.eB, with an increased capacity to cross the blood-brain barrier, thus offering a viable tool for a non-invasive and large-scale gene delivery in the central nervous system. Using this model, we report that widespread overexpression of human α-syn induced selective degeneration of dopaminergic (DA) neurons, an exacerbated neuroinflammatory response in the substantia nigra and a progressive manifestation of PD-like motor impairments. Interestingly, biochemical analysis revealed the presence of insoluble α-syn oligomers in the midbrain. Together, our data demonstrate that a single non-invasive systemic delivery of viral particles overexpressing α-syn prompted selective and progressive neuropathology resembling the early stages of PD. Our new in vivo model represents a valuable tool to study the role of α-syn in PD pathogenesis and in the selective vulnerability of nigral DA neurons; and offers the opportunity to test new strategies targeting α-syn toxicity for the development of disease-modifying therapies for PD and related disorders.

中文翻译：

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人α-突触核蛋白的非侵入性全身病毒递送模拟啮齿动物大脑中帕金森病的选择性和进行性神经病理学

α-突触核蛋白 (α-syn) 聚集成蛋白质神经元内包涵体，称为路易体 (LB)，是帕金森病 (PD) 和相关突触核蛋白病的神经病理学标志。然而，α-syn 内含物在 PD 发病机制中的确切作用仍然难以捉摸。这种知识的缺乏主要是由于缺乏能够概括神经退行性变不同阶段的最佳基于 α-syn 的动物模型。在这里，我们描述了一种新方法，用于全身递送携带人类α-syn的病毒颗粒，从而允许这种蛋白质在小鼠大脑中大规模过度表达。该方法基于新一代腺相关病毒 (AAV) AAV-PHP.eB 的使用，该病毒具有增强的穿过血脑屏障的能力，从而为非侵入性和大规模检测提供了可行的工具。 -中枢神经系统中规模的基因传递。使用该模型，我们报告人类 α-syn 的广泛过度表达诱导多巴胺能 (DA) 神经元的选择性变性、黑质中神经炎症反应的加剧以及 PD 样运动障碍的进行性表现。有趣的是，生化分析显示中脑中存在不溶性 α-syn 寡聚物。总之，我们的数据表明，过表达 α-syn 的病毒颗粒的单次非侵入性全身递送促进了类似于 PD 早期阶段的选择性和进行性神经病理学。我们的新体内模型是研究 α-syn 在 PD 发病机制和黑质 DA 神经元选择性脆弱性中的作用的宝贵工具；并提供了测试针对 α-syn 毒性的新策略的机会，以开发针对 PD 和相关疾病的疾病缓解疗法。