Dopamine, mutant synuclein, oxidative stress and inflammation

帕金森病是一种缓慢进展的退行性疾病， 症状包括静止性震颤、齿轮状强直和运动迟缓。疾病产生 黑质（SN）中多巴胺神经元的不变损失，具有标志性病理特征 在剩下的细胞中有激活的小胶质细胞和蛋白质细胞质内含物，称为Lewy小体。 神经元流行病学数据支持基因-环境相互作用是导致 散发性PO病例比例最大。PO的关键问题之一是识别 启动触发机制及其损伤部位。阐明这一机制的努力 通过毒物（例如，MPTP百草枯鱼藤酮）损伤，氧化应激， 突触前和路易体组成蛋白α-突触核蛋白（SYN）的转换中的遗传缺陷， 和胞质多巴胺的参与。使用建立的野生型（wtSYN+/+）和 突变SYN（dmSYN+/+）在OA产生细胞中的过表达，我们将解决这一假设， SYN过表达的早期效应是增加小胶质细胞活化和促炎性细胞因子。 导致突触前功能障碍。我们进一步证明，wtSYN和dmSYN 激活小胶质细胞的差异，但都导致增加醌氧化反应。 提出了三个目标来检验这一假设：Ai m 1。小胶质细胞活化的表征和 过表达野生型（wtSYN+/+）或双突变SYN（dmSYN+/+）的小鼠中的突触前功能; 目标2.对wtSYN和dmSYN的促炎反应的表征：目的3。考试 醌介导的氧化应激在小胶质细胞活化中的作用。我们将利用几个独特的 转基因小鼠模型，包括过表达wIld型SYN的wtSYN+/+， 过表达突变体SYN、wtSYN+/+：：AREhPLAP和dmSYN+/+：：AREhPLAP，其过表达 SYN在能够报告醌介导的应激的小鼠的背景中。这些研究将 产生明确和可解释的数据，关于小胶质细胞在突触前损伤中的作用， 的SYN。 帕金森病（PD）是第二常见的神经退行性疾病， 患者及其护理人员。本项目的目标是评估在 PD期间的大脑。我们的工作集中在组织培养和PO的动物模型上， 促炎分子和小胶质细胞在疾病发生和发展中的作用。特别 我们将研究PD的早期变化。这些研究的结果可能会导致识别 PD的潜在治疗方法。

Parkinson's disease is a slowly progressive degenerative disorder with classic motor symptoms that include resting tremor, cogwheel rigidity and bradykinesia. The disease produces invariant loss of dopamine neurons in the substantia nigra (SN) with the hallmark pathological features of activated microglia and proteinaceous cytoplasmic inclusions called Lewy bodies in the remaining neurons. Epidemiological data supports that gene-environment interactions are responsible for the largest proportion of sporadic PO cases. One of the key issues in PO is the identification of the initiating triggering mechanism(s) and the locus of its injury. Efforts to elucidate th·ls mechanism have been aided by the linkage between toxicant (e.g., MPTP, paraquat. rotenone) injury, oxidative stress, inherited defects in turnover of the presynaptic and Lewy Body constituent protein a-synuclein (SYN), and involvement of cytosolic dopamine. Using established animal models of wild-type (wtSYN+/+) and mutant SYN (dmSYN+/+) overexpression in OA producing cells we will address the hypothesis that an early effect of SYN overexpression is increased microglial activation and proinflammatory processes leading to presynaptic dysfunction. We further posit that wtSYN and dmSYN activate microglia differentially but both result in an increased quinone oxidant response. Three aims are proposed to test this hypothesis: Ai m 1. Characterization of microglial activation and presynaptic function in mice overexpressing wild-type (wtSYN+/+) or double-mutant SYN (dmSYN+/+); Aim 2. Characterization of the proinflammatory response to wtSYN and dmSYN: Aim 3. Examination of the role of quinone-mediated oxidative stress in microglial activation. We will utilize several unique transgenic mouse models including wtSYN+/+ that overexpress wIld-type SYN, dmSYN+/+ that overexpress mutant SYN, wtSYN+/+::AREhPLAP and dmSYN+/+::AREhPlAP which overexpress SYN in the background of a mouse capable of reporting quinone-mediated stress. These studies will produce clear and interpretable data concerning the role of microglia in the presynaptic injury elicited by SYN. Parkinson 's Disease (PO) is the second most common neurodegenerative disease and impacts both patients and their caregivers. The goal of this project is to evaluate the progressive changes in the brain during PD. We focus our work on both tissue culture and animal models of PO and ask what is the role of pro-inflammatory molecules and microglia in disease initiation and progression . Particularly we will study early changes in PD. The results of these studies may lead to the identIfication of potential therapies for PD.