Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons
Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons
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DOI：
10.1074/jbc.m308947200
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发表时间：
2003-10-31
影响因子：
4.8
通讯作者：
Shen, J
中科院分区：
文献类型：
--
作者：
Goldberg, MS;Fleming, SM;Shen, J
帕金蛋白功能缺失突变是早发性家族性帕金森病的主要病因。为了研究帕金蛋白功能缺失导致帕金森病的致病机制，我们构建了一种帕金蛋白种系破坏的小鼠模型。帕金蛋白基因敲除（Parkin -/-）小鼠能够存活，并且大脑形态大致正常。体内定量微透析显示，Parkin -/-小鼠纹状体中细胞外多巴胺浓度升高。对中型纹状体棘状神经元进行的细胞内记录表明，诱导突触反应需要更大的电流，这表明在缺乏帕金蛋白的情况下突触兴奋性降低。此外，Parkin -/-小鼠在对黑质 - 纹状体通路功能障碍敏感的行为范式中表现出缺陷。然而，与帕金森病中黑质神经元大量缺失的特征不同，直到24个月龄，Parkin -/-小鼠黑质中的多巴胺能神经元数量都是正常的。先前被确定为帕金蛋白E3泛素连接酶活性底物的CDCrel - 1、突触核蛋白 - 1和α - 突触核蛋白的稳态水平在Parkin -/-小鼠大脑中没有改变。这些发现共同首次证明了帕金蛋白在多巴胺调节和黑质 - 纹状体功能中的新作用，以及帕金蛋白在小鼠黑质神经元存活中的非关键作用。
Loss-of-function mutations in parkin are the major cause of early-onset familial Parkinson's disease. To investigate the pathogenic mechanism by which loss of parkin function causes Parkinson's disease, we generated a mouse model bearing a germline disruption in parkin. Parkin-/- mice are viable and exhibit grossly normal brain morphology. Quantitative in vivo microdialysis revealed an increase in extracellular dopamine concentration in the striatum of parkin-/- mice. Intracellular recordings of medium-sized striatal spiny neurons showed that greater currents are required to induce synaptic responses, suggesting a reduction in synaptic excitability in the absence of parkin. Furthermore, parkin-/- mice exhibit deficits in behavioral paradigms sensitive to dysfunction of the nigrostriatal pathway. The number of dopaminergic neurons in the substantia nigra of parkin-/- mice, however, is normal up to the age of 24 months, in contrast to the substantial loss of nigral neurons characteristic of Parkinson's disease. Steady-state levels of CDCrel-1, synphilin-1, and alpha-synuclein, which were identified previously as substrates of the E3 ubiquitin ligase activity of parkin, are unaltered in parkin-/- brains. Together these findings provide the first evidence for a novel role of parkin in dopamine regulation and nigrostriatal function, and a non-essential role of parkin in the survival of nigral neurons in mice.