Integrating pathogenic mechanisms in Parkinson's disease

摘要 α-突触核蛋白表达、c-Abl激活和神经元谷胱甘肽水平分别为 被认为是帕金森病的促成因素，但这些因素是如何相互作用的 人们对此知之甚少。这一知识差距具有基础性和治疗性意义，因为 这些相互作用可能定义了帕金森病的最终共同途径 发病机制。谷胱甘肽被神经元用来清除活性氧 修复氧化损伤的蛋白质。在帕金森病中，α-1的积聚 突触核蛋白寡聚体与谷胱甘肽耗竭、氧化应激和神经元相关 死亡。α-突触核蛋白聚集体的形成由c-Abl促进，c-Abl是一种酪氨酸激酶，在 被氧化应激激活。我们假设α-突触核蛋白聚集体推动 通过金属催化的过程形成的活性氧物种，以及 谷胱甘肽耗竭导致α-突触核蛋白聚集和c-Abl激活 前馈的方式。我们将使用细胞培养模型来验证这一假设，在该模型中，α- 突触核蛋白聚集体、硫醇氧化还原状态和c-Abl活性可以独立控制 并受到监控。我们还将使用两个新的双转基因小鼠品系， α-突触核蛋白聚集及其相关病理在(1)背景下的评价 NADPH氧化酶活性降低，以及(2)神经元谷胱甘肽水平降低。这些 菌株，结合新的药理工具，将使我们能够确定病因- 神经元氧化应激、α-突触核蛋白聚集和c-Abl的作用关系 活体内活动。 1

ABSTRACT α-synuclein expression, c-Abl activation, and neuronal glutathione levels are each recognized as contributory factors in Parkinson’s disease, but how these factors interact is poorly understood. This knowledge gap is of basic and therapeutic relevance because these interactions may define a final common pathway in Parkinson’s disease pathogenesis. Glutathione is used by neurons to both scavenge reactive oxygen species and repair oxidatively damage proteins. In Parkinson’s disease, the accumulation of α- synuclein oligomers is associated with glutathione depletion, oxidative stress, and neuronal death. α-synuclein aggregate formation is promoted by c-Abl, a tyrosine kinase that is in turn activated by oxidative stress. We hypothesize that α-synuclein aggregates drive reactive oxygen species formation through metal-catalyzed processes, and that the resulting glutathione depletion contributes to α-synuclein aggregation and c-Abl activation in a feed-forward manner. We will test this hypothesis using cell culture models in which α- synuclein aggregates, thiol redox state, and c-Abl activity can be independently manipulated and monitored. We will also employ two novel double-transgenic mouse strains that permit evaluation of a-synuclein aggregation and its associated pathology in the setting of (1) deficient NADPH oxidase activity, and (2) reduced neuronal glutathione levels. These strains, in combination with novel pharmacological tools, will allow us to identify cause- effect relationships between neuronal oxidative stress, α-synuclein aggregation, and c-Abl activity in vivo. 1