Abstract：
Parkinson\'s disease (PD) is a common neurodegenerative disorder that is affecting an increasing number of older adults. Although PD is mostly sporadic, genetic mutations have been found in cohorts of families with a history of familial PD (FPD). The first such mutation linked to FPD causes a point mutation (A53T) in α-synuclein (α-syn), a major component of Lewy bodies, which are a classical pathological hallmark of PD. These findings suggest that α-syn is an important contributor to the development of PD. In our previous study, we developed an adenoviral mouse model of PD and showed that the expression of wild-type (WT) α-syn or a mutant form with an increased propensity to aggregate, designated as WT-CL1 α-syn, could be used to study how α-syn aggregation contributes to PD. In this study, we established a transgenic mouse model that conditionally expresses WT or WT-CL1 α-syn in dopaminergic (DA) neurons and found that the expression of either WT or WT-CL1 α-syn was associated with an age-dependent degeneration of DA neurons and movement dysfunction. Using this model, we were able to monitor the process of α-syn aggregate formation and found a correlation between age and the number and sizes of α-syn aggregates formed. These results provide a potential mechanism by which age-dependent α-syn aggregation may lead to the formation of Lewy bodies in PD pathogenesis.
摘要：
帕金森病（PD）是一种常见的神经退行性疾病，正在影响越来越多的老年人。虽然PD大多是零星的，在有家族性PD(FPD)病史的家族队列中发现了基因突变.与FPD相关的第一个此类突变在α-突触核蛋白（α-syn）中引起点突变（A53T），路易体的主要组成部分，这是PD的经典病理标志。这些发现表明α-syn是PD发展的重要因素。在我们之前的研究中,我们开发了PD的腺病毒小鼠模型，并显示野生型（WT）α-syn或突变形式的表达具有增加的聚集倾向，命名为WT-CL1α-syn，可用于研究α-syn聚集如何促进PD。在这项研究中,我们建立了一个转基因小鼠模型，该模型在多巴胺能（DA）神经元中有条件表达WT或WT-CL1α-syn，并发现WT或WT-CL1α-syn的表达与DA神经元的年龄依赖性变性和运动功能障碍有关。使用这个模型，我们能够监测α-syn聚集体形成的过程，并发现年龄与形成的α-syn聚集体的数量和大小之间存在相关性。这些结果提供了一种潜在的机制，通过该机制，年龄依赖性α-syn聚集可能导致PD发病机理中路易体的形成。
