A Rat Model of Progressive Nigral Neurodegeneration Induced by the Parkinson's Disease-Associated G2019S Mutation in LRRK2
A Rat Model of Progressive Nigral Neurodegeneration Induced by the Parkinson's Disease-Associated G2019S Mutation in LRRK2
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DOI：
10.1523/jneurosci.5092-10.2011
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发表时间：
2011-01-19
影响因子：
5.3
通讯作者：
Aebischer, Patrick
中科院分区：
文献类型：
--
作者：
Dusonchet, Julien;Kochubey, Olexiy;Aebischer, Patrick
富含亮氨酸重复序列激酶2（LRRK2）基因中的G2019S突变是帕金森病（PD）最常见的遗传原因，在常染色体显性遗传家族性和散发性PD病例中占很大比例。我们在本研究中的目的是产生突变G2019S LRRK2发病机制的哺乳动物模型，该模型再现PD的强大黑质神经变性特征。我们开发了腺病毒载体来驱动成年大鼠黑质纹状体系统中全长野生型或突变型G2019S人LRRK2的神经元特异性表达。野生型LRRK2不诱导任何显著的神经元损失。相反，在相同的条件和表达水平下，G2019S突变体LRRK2导致黑质多巴胺能神经元的进行性变性。我们的数据提供了一种新的PD大鼠模型，基于一种流行的遗传原因，在适合测试神经保护策略的快速时间范围内再现了疾病的主要特征。
The G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene is the most common genetic cause of Parkinson's disease (PD), accounting for a significant proportion of both autosomal dominant familial and sporadic PD cases. Our aim in the present study is to generate a mammalian model of mutant G2019S LRRK2 pathogenesis, which reproduces the robust nigral neurodegeneration characteristic of PD. We developed adenoviral vectors to drive neuron-specific expression of full-length wild-type or mutant G2019S human LRRK2 in the nigrostriatal system of adult rats. Wild-type LRRK2 did not induce any significant neuronal loss. In contrast, under the same conditions and levels of expression, G2019S mutant LRRK2 causes a progressive degeneration of nigral dopaminergic neurons. Our data provide a novel rat model of PD, based on a prevalent genetic cause, that reproduces a cardinal feature of the disease within a rapid time frame suitable for testing of neuroprotective strategies.