Parkinson's disease is one of the most common movement disorders and is characterized by dopaminergic cell loss and the accumulation of pathological α-synuclein, but its precise pathogenetic mechanisms remain elusive. To develop disease-modifying therapies for Parkinson's disease, an animal model that recapitulates the pathology and symptoms of the disease, especially in the prodromal stage, is indispensable. As subjects with α-synuclein gene (SNCA) multiplication as well as point mutations develop familial Parkinson's disease and a genome-wide association study in Parkinson's disease has identified SNCA as a risk gene for Parkinson's disease, the increased expression of α-synuclein is closely associated with the aetiology of Parkinson's disease. In this study we generated bacterial artificial chromosome transgenic mice harbouring SNCA and its gene expression regulatory regions in order to maintain the native expression pattern of α-synuclein. Furthermore, to enhance the pathological properties of α-synuclein, we inserted into SNCA an A53T mutation, two single-nucleotide polymorphisms identified in a genome-wide association study in Parkinson's disease and a Rep1 polymorphism, all of which are causal of familial Parkinson's disease or increase the risk of sporadic Parkinson's disease. These A53T SNCA bacterial artificial chromosome transgenic mice showed an expression pattern of human α-synuclein very similar to that of endogenous mouse α-synuclein. They expressed truncated, oligomeric and proteinase K-resistant phosphorylated forms of α-synuclein in the regions that are specifically affected in Parkinson's disease and/or dementia with Lewy bodies, including the olfactory bulb, cerebral cortex, striatum and substantia nigra. Surprisingly, these mice exhibited rapid eye movement (REM) sleep without atonia, which is a key feature of REM sleep behaviour disorder, at as early as 5 months of age. Consistent with this observation, the REM sleep-regulating neuronal populations in the lower brainstem, including the sublaterodorsal tegmental nucleus, nuclei in the ventromedial medullary reticular formation and the pedunculopontine nuclei, expressed phosphorylated α-synuclein. In addition, they also showed hyposmia at 9 months of age, which is consistent with the significant accumulation of phosphorylated α-synuclein in the olfactory bulb. The dopaminergic neurons in the substantia nigra pars compacta degenerated, and their number was decreased in an age-dependent manner by up to 17.1% at 18 months of age compared to wild-type, although the mice did not show any related locomotor dysfunction. In conclusion, we created a novel mouse model of prodromal Parkinson's disease that showed RBD-like behaviour and hyposmia without motor symptoms.

中文翻译：

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α-突触核蛋白BAC转基因小鼠表现出RBD样的行为和低渗：帕金森氏病的前驱模型。

帕金森氏病是最常见的运动障碍之一，其特征是多巴胺能细胞丢失和病理性α-突触核蛋白的积累，但其确切的致病机制仍难以捉摸。为了开发针对帕金森氏病的疾病缓解疗法，必不可少的动物模型必须概括疾病的病理学和症状，尤其是在前驱阶段。随着具有α-突触核蛋白基因（SNCA）增殖和点突变的受试者发展家族性帕金森氏病，并且针对帕金森氏病的全基因组关联研究已确定SNCA是帕金森氏病的危险基因，α-突触核蛋白的表达增加与之密切相关。与帕金森氏病的病因有关。在这项研究中，我们生成了具有SNCA及其基因表达调控区的细菌人工染色体转基因小鼠，以维持α-突触核蛋白的天然表达模式。此外，为了增强α-突触核蛋白的病理特性，我们在SNCA中插入了一个A53T突变，在帕金森氏病的全基因组关联研究中发现的两个单核苷酸多态性和一个Rep1多态性，所有这些都是家族性帕金森氏病的原因或增加散发性帕金森氏病的风险。这些A53T SNCA细菌人工染色体转基因小鼠显示出与内源性小鼠α-突触核蛋白非常相似的人α-突触核蛋白的表达模式。他们表示被截断，在帕金森氏病和/或痴呆伴路易小体（包括嗅球，大脑皮层，纹状体和黑质）中特别受影响的区域，α-突触核蛋白的低聚和耐蛋白酶K磷酸化形式。出人意料的是，这些小鼠早在5个月大时就表现出快速眼动（REM）睡眠，而没有失聪，这是REM睡眠行为障碍的关键特征。与此观察结果一致，下脑干中的REM睡眠调节神经元种群，包括背侧睑板下核，腹膜延髓网状结构中的核和足小神经元核，均表达了磷酸化的α-突触核蛋白。此外，他们在9个月大时还表现为低渗，这与嗅球中磷酸化α-突触核蛋白的大量积累是一致的。尽管野生型小鼠没有显示任何相关的运动功能障碍，但黑质致密部中的多巴胺能神经元退化，与野生型相比，它们的数量在18个月大时以年龄依赖的方式减少了高达17.1％。总之，我们创建了一种前驱性帕金森氏病的新型小鼠模型，该模型显示出RBD样的行为和低渗血症，而没有运动症状。