Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an α-synuclein rat model of Parkinson's disease
Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an α-synuclein rat model of Parkinson's disease
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DOI：
10.1073/pnas.0405313101
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发表时间：
2004-12-14
影响因子：
11.1
通讯作者：
Aebischer, P
中科院分区：
文献类型：
--
作者：
Lo Bianco, C;Schneider, BL;Aebischer, P
帕金森病（PD）的特征在于中脑多巴胺神经元的进行性损失和称为Lewy小体的细胞质内含物的存在。包括α-突触核蛋白和parkin在内的几个基因的突变与家族性PD有关。帕金E3连接酶活性的丧失导致早发性常染色体隐性青少年帕金森病的多巴胺能神经元变性，这表明帕金对多巴胺神经元存活的关键作用。为了评估parkin在PD发病机制中的潜在神经保护作用，我们测试了野生型大鼠parkin的过表达是否可以在PD的大鼠慢病毒模型中保护突变的人A30 P α-突触核蛋白的毒性。过度表达parkin的动物表现出α-突触核蛋白诱导的神经病理学显著减少，包括黑质中酪氨酸羟化酶阳性细胞体的保存和纹状体中酪氨酸羟化酶阳性神经末梢的保留。帕金介导的神经保护作用与过度磷酸化的α-突触核蛋白内含物的增加有关，这表明帕金在路易体的发生中发挥着关键作用。这些结果表明，parkin基因治疗可能是一个有前途的候选治疗PD。
Parkinson's disease (PD) is characterized by a progressive loss of midbrain dopamine neurons and the presence of cytoplasmic inclusions called Lewy bodies. Mutations in several genes including alpha-synuclein and parkin have been linked to familial PD. The loss of parkin's E3-ligase activity leads to dopaminergic neuronal degeneration in early-onset autosomal recessive juvenile parkinsonism, suggesting a key role of parkin for dopamine neuron survival. To evaluate the potential neuroprotective role of parkin in the pathogenesis of PD, we tested whether overexpression of wild-type rat parkin could protect against the toxicity of mutated human A30P alpha-synuclein in a rat lentiviral model of PD. Animals overexpressing parkin showed significant reductions in alpha-synuclein-induced neuropathology, including preservation of tyrosine hydroxylase-positive cell bodies in the substantia nigra and sparing of tyrosine hydroxylase-positive nerve terminals in the striatum. The parkin-mediated neuroprotection was associated with an increase in hyperphosphorylated alpha-synuclein inclusions, suggesting a key role for parkin in the genesis of Lewy bodies. These results indicate that parkin gene therapy may represent a promising candidate treatment for PD.