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

帕金森病和多巴胺神经元的不同易感性

• 批准号: 7487570
• 负责人: Bahareh Behrouz
• 金额: $ 2.51万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-18 至 2008-12-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7487570
• 关键词: Adenovirus Vector; Affect; Aftercare; Biological Assay; Body Regions; Complex; Coupled; Data; Dopamine; Hypothalamic structure; Immunohistochemistry; Measures; Messenger RNA; Metabolism; Midbrain structure; Modeling; Motor; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathway interactions; Pattern; Physiological; Play; Population; Predisposition; Presynaptic Terminals; Proteasome Inhibition; Protein Overexpression; Proteins; Recombinants; Recovery; Resistance; Role; Symptoms; Testing; Time; TimeLine; Toxic effect; Translating; Western Blotting; dopaminergic neuron; in vivo; inhibitor/antagonist; knock-down; mitochondrial oxidative dysfunction; motor impairment; mouse model; neuron loss; neuronal cell body; neurotoxicity; parkin gene/protein; parkin protein; prevent; protein degradation; protein expression; research study; response; synuclein; ubiquitin-protein ligase

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.

描述（由申请人提供）：帕金森病（PD）是一种使人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变性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。异常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中受到的影响程度不同。事实上，当中脑黑纹状体多巴胺神经元严重丢失时，下丘脑结节基底多巴胺神经元保持完整。我们的初步数据表明，在PD小鼠模型中，当这些多巴胺神经元群体暴露于复合I抑制时，它们也有类似的易感性模式。此外，我们已经排除了几个外在因素先前假设的基础上这种差异的易感性。我们还证明，黑质纹状体和结节状基底多巴胺神经元对复合体I抑制有相似的初始反应，但只有结节状基底多巴胺神经元能够恢复。这次复苏的时间是有特点的，而且非常迅速。我们的初步数据还表明，蛋白parkin可能参与了这种差异的易感性。与黑质纹状体多巴胺神经元相比，结节基底多巴胺神经元细胞体区域的组成性parkin mRNA水平更高。此外，当结节基底神经元对复合物I抑制反应恢复时，parkin mRNA水平也显著升高。Parkin是一种E3连接酶，可标记错误折叠和异常蛋白进行降解，并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。提出的实验将确定是否在结节基底多巴胺神经元中较高水平的帕金保护它们免受复合体I抑制。这将通过降低结节基底多巴胺神经元中parkin mRNA和蛋白的表达并确定它们是否易受复合体I抑制来确定。此外，拟议的研究将确定增加黑质纹状体多巴胺神经元中的parkin表达是否会保护它们免受复合物I抑制剂的毒性。提出的实验将增强我们对多巴胺能神经元对复合物I抑制的不同敏感性的理解。该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。