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首页> 外文期刊>Experimental Neurology >Comparison of the behavioural and histological characteristics of the 6-OHDA and α-synuclein rat models of Parkinson's disease
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Comparison of the behavioural and histological characteristics of the 6-OHDA and α-synuclein rat models of Parkinson's disease

机译：帕金森氏病6-OHDA和α-突触核蛋白大鼠模型的行为和组织学特征比较

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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.
机译：帕金森氏病（PD）相关模型的开发对于更好地了解人类疾病的病理过程以及评估治疗干预的有希望的目标至关重要。迄今为止，大多数临床前研究已经在成熟的啮齿动物和非人类灵长类动物模型中进行，使用6-羟基多巴胺（6-OHDA）或1-甲基-4-苯基-1,2,3,6进行注射-四羟基吡啶（MPTP）。使用腺相关病毒（AAV）载体过度表达引起疾病的蛋白质α-突触核蛋白（α-syn），提供了一种可概括人类疾病许多特征的新颖模型。在本研究中，我们将AAV-α-syn大鼠模型与通过纹状体（部分病变）或前脑内侧束（完整病变）注射6-OHDA损害黑质纹状体途径的模型进行了比较。随时间变化的行为变化检查显示出运动障碍的不同进展和程度。有趣的是，在毒素模型和AAV-α-syn模型中，多巴胺（DA）神经元的丢失都很明显。但是，对于同等水平的运动异常，发现过表达α-syn的动物表现出更少的细胞和终末丢失。仅在α-syn大鼠模型中观察到突出且持续的轴突病理。我们建议，虽然神经元和终末损失主要是基于毒素的模型中的行为障碍，但类似的运动障碍是由AAV-α-syn模型中剩余的黑质纹状体神经元的细胞死亡和功能障碍导致的。虽然已经开发了两种模型来模拟DA神经元缺乏，但它们在时间和神经病理学特征上有所不同，并复制了人类疾病病理生理学的不同方面。这项研究表明，AAV-α-syn模型比其他两个6-OHDA损伤模型中的任何一个更能复制人类病理学。

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