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

描述(申请人提供)：帕金森氏病(PD)是一种衰弱的神经退行性疾病，会导致严重的运动障碍。黑质纹状体多巴胺神经元的进行性退化是这些运动症状的基础，目前还没有办法阻止或减缓这种神经元的丧失。多巴胺代谢异常被认为是这些神经元退化的基础。然而，帕金森病患者并不是所有的多巴胺神经元都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，但下丘脑结节漏斗中的多巴胺神经元保持完好。我们的初步数据显示，在帕金森病小鼠模型中，当这些多巴胺神经元群体暴露于复杂的I抑制时，它们的易感性模式类似。此外，我们已经排除了之前假设的几个外部因素，这些因素是这种差异敏感性的基础。我们还证明了黑质纹状体和漏斗结节多巴胺神经元对复合体I的抑制有相似的初始反应，但只有漏斗结节多巴胺神经元能够恢复。这一复苏的时间表已经确定，而且非常迅速。我们的初步数据还表明，Parkin蛋白可能参与了这种不同的易感性。与黑质纹状体多巴胺神经元的胞体区域相比，漏斗状结节多巴胺神经元胞体区域的组成性parkin mRNA水平更高。此外，在结节漏斗神经元对复合体I抑制反应恢复的关键时间点，parkin mRNA水平也显著增加。Parkin是一种E3连接酶，标记错误折叠和异常的蛋白质进行降解，在多种神经毒性模型中发挥保护作用，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。拟议的实验将确定漏斗状结节多巴胺神经元中较高水平的parkin是否能保护它们免受复合体I的抑制。这将通过降低漏斗结节多巴胺神经元中parkin的mRNA和蛋白的表达，并确定它们是否对复合体I的抑制敏感来确定。此外，拟议的研究将确定在黑质纹状体多巴胺神经元中增加parkin的表达是否会保护它们免受复合体I抑制剂的毒性。这些实验将加深我们对多巴胺能神经元对复合体I抑制反应的不同敏感性的理解。这一结果可能进一步转化为神经保护策略，可以防止帕金森病患者多巴胺神经元的持续退化。

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.