Wallenberg Neuroscience Center, Department of Experimental Medical Sciences, Lund University, BMC A11, Lund 22184, Sweden.
Exp Neurol. 2012 May;235(1):306-15. doi: 10.1016/j.expneurol.2012.02.012. Epub 2012 Feb 25.
Development of relevant models of Parkinson's disease (PD) is essential for a better understanding of the pathological processes underlying the human disease and for the evaluation of promising targets for therapeutic intervention. To date, most pre-clinical studies have been performed in the well-established rodent and non-human primate models using injection of 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6-tetrahydroxypyridine (MPTP). Overexpression of the disease-causing protein α-synuclein (α-syn), using adeno-associated viral (AAV) vectors, has provided a novel model that recapitulates many features of the human disease. In the present study we compared the AAV-α-syn rat model with models where the nigro-striatal pathway is lesioned by injection of 6-OHDA in the striatum (partial lesion) or the medial forebrain bundle (full lesion). Examination of the behavioural changes over time revealed a different progression and magnitude of the motor impairment. Interestingly, dopamine (DA) neuron loss is prominent in both the toxin and the AAV-α-syn models. However, α-syn overexpressing animals were seen to exhibit less cell and terminal loss for an equivalent level of motor abnormalities. Prominent and persistent axonal pathology is only observed in the α-syn rat model. We suggest that, while neuronal and terminal loss mainly accounts for the behavioural impairment in the toxin-based model, similar motor deficits result from the combination of cell death and dysfunction of the remaining nigro-striatal neurons in the AAV-α-syn model. While the two models have been developed to mimic DA neuron deficiency, they differ in their temporal and neuropathological characteristics, and replicate different aspects of the pathophysiology of the human disease. This study suggests that the AAV-α-syn model replicates the human pathology more closely than either of the other two 6-OHDA lesion models.
帕金森病（PD）相关模型的开发对于更好地理解人类疾病的病理过程以及评估有前途的治疗靶点至关重要。迄今为止，大多数临床前研究都是在成熟的啮齿动物和非人类灵长类动物模型中进行的，使用的方法是注射 6-羟多巴胺（6-OHDA）或 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）。使用腺相关病毒（AAV）载体过表达致病蛋白α-突触核蛋白（α-syn），提供了一种新的模型，可以重现人类疾病的许多特征。在本研究中，我们将 AAV-α-syn 大鼠模型与通过向纹状体注射 6-OHDA（部分损伤）或内侧前脑束（完全损伤）损伤黑质纹状体通路的模型进行了比较。随着时间的推移，对行为变化的检查揭示了运动障碍的不同进展和程度。有趣的是，在毒素和 AAV-α-syn 模型中，多巴胺（DA）神经元的丢失都很明显。然而，与同等水平的运动异常相比，过表达α-syn 的动物表现出较少的细胞和终末丢失。只有在α-syn 大鼠模型中才观察到明显和持续的轴突病理学。我们认为，虽然神经元和终末丢失主要导致毒素模型中的行为损伤，但在 AAV-α-syn 模型中，由于剩余黑质纹状体神经元的细胞死亡和功能障碍的组合，也会导致类似的运动缺陷。虽然这两种模型都是为了模拟 DA 神经元缺乏而开发的，但它们在时间和神经病理学特征上有所不同，并且复制了人类疾病病理生理学的不同方面。本研究表明，与其他两种 6-OHDA 损伤模型相比，AAV-α-syn 模型更能模拟人类的病理学。
