Progressive neurodegenerative and behavioural changes induced by AAV-mediated overexpression of α-synuclein in midbrain dopamine neurons
Progressive neurodegenerative and behavioural changes induced by AAV-mediated overexpression of α-synuclein in midbrain dopamine neurons
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DOI：
10.1016/j.nbd.2011.12.013
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发表时间：
2012-03-01
影响因子：
6.1
通讯作者：
Bjorklund, A.
中科院分区：
文献类型：
--
作者：
Decressac, M.;Mattsson, B.;Bjorklund, A.
帕金森氏病(PD)的特征是黑质多巴胺神经元的进行性丢失和突触核素病的存在。利用病毒载体在体内过表达α-突触核蛋白，为建立啮齿动物帕金森病样病理模型提供了有趣的可能性。然而，到目前为止所做的尝试都没有显示出一致的行为表型和明显的多巴胺神经变性。使用更有效的腺相关病毒(AAV)载体构建，其中包括WPRE增强子元件，并使用神经元特异性突触素-1启动子来驱动人野生型α-突触核蛋白的表达，我们现在已经能够在转导的中脑多巴胺神经元中实现α-突触核蛋白水平的增加，足以导致严重的运动功能障碍，伴随着参与多巴胺神经传递的蛋白的表达减少和黑质多巴胺神经元的时间依赖性丧失，在载体注射后2-4个月逐渐发展。与人类帕金森病一样，黑质细胞消失之前，纹状体轴突和终末出现退行性变化，营养不良的轴突和树突中出现α-突触核蛋白阳性包涵体，支持了α-突触核蛋白诱导的病理首先打击轴突和终末，然后进展到也累及细胞体的观点。在AAV-α-突触核蛋白治疗的动物中看到的变化的时间进程定义了与PD患者的症状前、早期症状和晚期阶段相匹配的疾病进展的不同阶段。这一模型为研究特定阶段的病理机制和确定与疾病早期或晚期相关的疾病修正治疗干预的靶点提供了新的有趣的可能性。(C)2011 Elsevier Inc.保留所有权利。
Parkinson's disease (PD) is characterised by the progressive loss of nigral dopamine neurons and the presence of synucleinopathy. Overexpression of alpha-synuclein in vivo using viral vectors has opened interesting possibilities to model PD-like pathology in rodents. However, the attempts made so far have failed to show a consistent behavioural phenotype and pronounced dopamine neurodegeneration. Using a more efficient adeno-associated viral (AAV) vector construct, which includes a WPRE enhancer element and uses the neuron-specific synapsin-1 promoter to drive the expression of human wild-type alpha-synuclein, we have now been able to achieve increased levels of alpha-synuclein in the transduced midbrain dopamine neurons sufficient to induce profound deficits in motor function, accompanied by reduced expression of proteins involved in dopamine neurotransmission and a time-dependent loss of nigral dopamine neurons, that develop progressively over 2-4 months after vector injection. As in human PD, nigral cell loss was preceded by degenerative changes in striatal axons and terminals, and the appearance of alpha-synuclein positive inclusions in dystrophic axons and dendrites, supporting the idea that alpha-synuclein-induced pathology hits the axons and terminals first and later progresses to involve also the cell bodies. The time-course of changes seen in the AAV-alpha-synuclein treated animals defines distinct stages of disease progression that matches the pre-symptomatic, early symptomatic, and advanced stages seen in PD patients. This model provides new interesting possibilities for studies of stage-specific pathologic mechanisms and identification of targets for disease-modifying therapeutic interventions linked to early or late stages of the disease. (C) 2011 Elsevier Inc. All rights reserved.