Parkin and differential susceptibility of dopamine neurons in Parkinson's disease

描述（由申请人提供）：帕金森病（PD）是一种导致严重运动障碍的衰弱性神经退行性疾病。黑质纹状体多巴胺神经元的进行性变性是这些运动症状的基础，目前没有办法阻止或减缓这种神经元的损失。异常的多巴胺代谢被认为是这些神经元退化的基础。然而，所有多巴胺神经元在PD中并没有受到相同程度的影响。事实上，虽然中脑黑质纹状体多巴胺神经元严重丢失，但下丘脑结节漏斗多巴胺神经元保持完整。我们的初步数据表明，在这些多巴胺神经元群体的易感性相似的模式，当他们暴露于复合物I抑制在PD的小鼠模型。此外，我们已经排除了几个外在因素，以前假设这种差异的易感性。我们还表明，黑质纹状体和tuberoinfundibular多巴胺神经元有一个类似的初始反应复杂的I抑制，但只有tuberoinfundibular多巴胺神经元能够恢复。这一复苏的时间轴已经确定，而且非常迅速。我们的初步数据还表明，蛋白parkin可能参与这种差异的易感性。组成型parkin mRNA水平较高的结节漏斗多巴胺神经元的细胞体区域相比，黑质纹状体多巴胺神经元的细胞体区域。此外，在关键的时间点，当tuberoinfundibular神经元显示恢复响应复合物I抑制，parkin mRNA水平也显着增加。Parkin是一种E3连接酶，其标记错误折叠和异常蛋白以进行降解，并在包括线粒体功能障碍、氧化损伤、突触核蛋白毒性和蛋白酶体抑制的几种神经毒性模型中起保护作用。拟议的实验将确定是否较高水平的parkin在tuberoinfundibular多巴胺神经元保护他们从复杂的I抑制。这将通过降低结节漏斗多巴胺神经元中parkin mRNA和蛋白质的表达并确定它们是否对复合物I抑制敏感来确定。此外，拟议的研究将确定是否增加黑质纹状体多巴胺神经元中的parkin表达将保护它们免受复合物I抑制剂的毒性。拟议的实验将提高我们的理解，多巴胺能神经元的差异敏感性，响应复合物I抑制。这些结果可能进一步转化为神经保护策略，可以防止PD中多巴胺神经元的持续变性。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a debilitating neurodegenerative disorder that causes severe motor impairments. Progressive degeneration of nigrostriatal dopamine neurons underlies these motor symptoms and there is currently no way to stop or slow this neuronal loss. Abnormal dopamine metabolism has been proposed to underlie the degeneration of these neurons. However, all dopamine neurons are not affected to the same extent in PD. In fact, while there is severe loss of midbrain nigrostriatal dopamine neurons, the hypothalamic tuberoinfundibular dopamine neurons remain intact. Our preliminary data demonstrates that a similar pattern of susceptibility in these dopamine neuronal populations when they are exposed to complex I inhibition in a mouse model of PD. Furthermore, we have ruled out several extrinsic factors previously hypothesized to underlie this differential susceptibility. We have also demonstrated that the nigrostriatal and tuberoinfundibular dopamine neurons have a similar initial response to complex I inhibition but that only tuberoinfundibular dopamine neurons are able to recover. The timeline of this recovery has been characterized and is very rapid. Our preliminary data also suggests that the protein parkin may be involved in this differential susceptibility. Constitutive parkin mRNA levels are higher in the cell body regions of tuberoinfundibular dopamine neurons when compared to cell body regions of nigrostriatal dopamine neurons. Furthermore, at the critical time point when tuberoinfundibular neurons show recovery in response to complex I inhibition, parkin mRNA levels also dramatically increase. Parkin is an E3 ligase that tags misfolded and abnormal proteins for degradation and plays a protective role in several models of neurotoxicity including mitochondrial dysfunction, oxidative damage, synuclein toxicity and proteasome inhibition. The proposed experiments will determine whether higher levels of parkin in the tuberoinfundibular dopamine neurons protect them from complex I inhibition. This will be determined by decreasing the expression of parkin mRNA and protein in tuberoinfundibular dopamine neurons and determining whether they become susceptible to complex I inhibition. Furthermore, the proposed studies will determine whether increasing parkin expression in the nigrostriatal dopamine neurons will protect them from complex I inhibitor toxicity. The proposed experiments will enhance our understanding of differential susceptibility of dopaminergic neurons in response to complex I inhibition. The results may be further translated into neuroprotective strategies that can prevent the ongoing degeneration of dopamine neurons in PD.