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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Nigrostriatal α-synucleinopathy induced by viral vector-mediated overexpression of human α-synuclein; A new primate model of Parkinson's disease
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Nigrostriatal α-synucleinopathy induced by viral vector-mediated overexpression of human α-synuclein; A new primate model of Parkinson's disease

机译：病毒载体介导的人α-突触核蛋白过表达诱导的黑纹状体α-突触核蛋白病；帕金森氏病的新灵长类动物模型

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摘要

We used a high-titer recombinant adeno-associated virus (rAAV) vector to express WT or mutant human a-synuclein in the substantia nigra of adult marmosets. The α-synuclein protein was expressed in 90-95% of all nigral dopamine neurons and distributed by anterograde transport throughout their axonal and dendritic projections. The transduced neurons developed severe neuronal pathology, including α-synuclein-positive cytoplasmic inclusions and granular deposits; swollen, dystrophic, and fragmented neuritis; and shrunken and pyknotic, densely α-synuclein-positive perikarya. By 16 wk posttransduction, 30-60% of the tyrosine hydroxylase-positive neurons were lost, and the tyrosine hydrox-ylase-positive innervation of the caudate nucleus and putamen was reduced to a similar extent. The rAAV-α-synuclein-treated monkeys developed a type of motor impairment, i.e., head position bias, compatible with this magnitude of nigrostriatal damage. rAAV vector-mediated α-synuclein gene transfer provides a trans-genie primate model of nigrostriatal α-synucleinopathy that is of particular interest because it develops slowly over time, like human Parkinson's disease (PD), and expresses neuropathological features (α-synuclein-positive inclusions and dystrophic neurites, in particular) that are similar to those seen in idiopathic PD. This model offers new opportunities for the study of pathogenetic mechanisms and exploration of new therapeutic targets of particular relevance to human PD.
机译：我们使用高滴度重组腺相关病毒（rAAV）载体在成年mar猴的黑质中表达野生型或突变型人α-突触核蛋白。 α-突触核蛋白蛋白在所有的黑色多巴胺神经元的90-95％中表达，并通过顺行转运分布在它们的整个轴突和树突状突起中。转导的神经元发展出严重的神经病理，包括α-突触核蛋白阳性细胞质内含物和颗粒沉积物。肿胀，营养不良和支离破碎的神经炎;以及收缩和强直的，密集的α-突触核蛋白阳性果核。到转导后第16周，酪氨酸羟化酶阳性神经元丢失了30-60％，尾状核和壳核的酪氨酸羟化酶阳性神经支配程度也有所降低。经rAAV-α-突触核蛋白处理的猴子出现了一种运动障碍，即头部位置偏斜，与这种黑纹状体损伤程度相适应。 rAAV载体介导的α-突触核蛋白基因转移提供了黑纹状体α-突触核蛋白病的灵长类灵长类灵长类动物模型，因为它随着时间的推移会缓慢发展，例如人类帕金森氏病（PD），并表达神经病理学特征（α-突触核蛋白-阳性夹杂物和营养不良的神经突，特别是），与特发性PD相似。该模型为研究致病机理和探索与人类PD特别相关的新治疗靶标提供了新的机会。

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