Progression of Neurotransmitter Dysreg in Mouse and Cell Models of PD

对家族性帕金森病（PD）基因突变的鉴定提供了 有可能深入了解疾病散发形式的机制。电流鼠标 基于两个这样的基因parkin和alpha-synucein中的缺失或突变的模型没有表现出 多巴胺能神经元变性然而，在我们中心内对其中两个模型的仔细审查， 揭示了行为（项目1），神经化学（项目2）和电生理（项目3）缺陷， 很可能模拟了在神经元变性之前进行性人类疾病过程的早期阶段。的 该中心的目标是建立在这种多学科的方法，以确定时间进程的进展 在多种遗传模型的PD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PD有关。通过阐明造成这些缺陷的机制， 希望在失去重要的治疗靶点之前， 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 在parkin外显子3 KO和α-突触核蛋白过表达小鼠中， 考虑到DA促进氧化应激并最终导致细胞死亡的潜力。我们将确定：1）如果 观察结果推广到parkin外显子2 KO小鼠，推广到小鼠遗传学中心生产的小鼠， 表达帕金突变的果蝇和其他α-突触核蛋白模型， 过度表达2）除了DA之外的其他递质系统是否也被破坏， PD中非运动症状的重要性，在项目5中研究，并在项目1中建模; 3）如果增加 细胞外DA是由囊泡释放、再摄取、逆向转运或代谢的失调引起的; 4)考虑到帕金蛋白和突触核蛋白与突触囊泡成分的联系（项目4）， 我们的观察结果可以用突触囊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.