Progression of Neurotransmitter Dysreg in Mouse and Cell Models of PD

识别导致家族性帕金森氏病(PD)的基因突变提供了 有可能深入了解这种零星形式的疾病背后的机制。当前鼠标 基于parkin和α-突触素这两个这样的基因的缺失或突变的模型没有显示 多巴胺能神经元变性。然而，我们中心内部对其中两个型号的仔细审查， 暴露出行为(项目1)、神经化学(项目2)和电生理(项目3)缺陷， 可能是进行性人类疾病过程的早期阶段的模型，在神经元退化之前。这个 该中心的目标是在这种多学科方法的基础上确定进展的时间进程 帕金森病的多种遗传模型中的细胞功能障碍，以确定共同的缺陷，因为这些是最 可能与散发性帕金森病有关。通过阐明造成这些缺陷的机制，我们 希望发现治疗靶点，以防止疾病的进展，之前损失显著 多巴胺(DA)神经元的数量。这个项目建立在我们的观察基础上，纹状体细胞外DA Parkin外显子3 KO和α-突触核蛋白过度表达的小鼠水平升高，这是一个有意义的发现 考虑到DA可能促进氧化应激，并最终导致细胞死亡。我们将确定：1)如果 观察推广到Parkin外显子2 KO小鼠，小鼠，由小鼠遗传核心产生， 表达Parkin突变可导致果蝇DA细胞死亡，并与其他模型的α-突触核蛋白有关 过度表达2)除了DA以外的发射机系统是否也被中断 非运动症状在帕金森病中的重要性，在项目5中研究，并在项目1中建模；3)如果增加 细胞外DA是囊泡释放、重摄取、反向转运或代谢失调的结果； 4)鉴于parkin和突触核蛋白与突触小泡成分之间的联系(项目4)， 我们的观察可以用突触小泡循环的中断来解释。

The identification of genetic mutations responsible for familial forms of Parkinson's disease (PD) offers the potential to glean insight into the mechanisms underlying the sporadic form of the disease. Currentmouse models based on deletions or mutations in two such genes, parkin and alpha-synucein, do not exhibit dopaminergic neuron degeneration. However, close scrutiny of two of these models within our Center, has revealed behavioral (Project 1), neurochemical (Project 2) and electrophysiological (Project 3) deficits, which likely model early stages of the progressive human disease process, prior to neuronal degeneration. The goal of the Center is to build on this multidisciplinary approach to determine the time-course of progression of cell dysfunction in multiple genetic models of PD in order to identify common deficits, since these are most likely to be of relevance to sporadic PD. By elucidating the mechanisms responsible for these deficits we hope to uncover therapeutic targets for preventing disease progression, prior to the loss of significant numbers of dopamine (DA) neurons. This project builds upon our observation that striatal extracellular DA levels are elevated in parkin exon 3 KO and alpha-synuclein over-expressing mice, a finding of significance given the potential of DA to promote oxidative stress and, ultimately, cell death. We will determine: 1) if this observation generalizes to parkin exon 2 KO mice, to mice, produced by the Mouse Genetics Core, expressing a parkin mutation shown to cause DA cell death in flies, and to other models of alpha-synuclein over-expression 2) whether transmitter systems other than DA are also disrupted, given the recognized importance of non-motor symptoms in PD, studied in Project 5, and modeled in Project 1; 3) if the increased extracellular DA results from dysregulation of vesicular release, reuptake, reverse transport or metabolism; 4) whether, given the association of parkin and synuclein with components of synaptic vesicles (Project 4), our observations can be explained by disruption of synaptic vesicle cycling.