Pathological interactions of a-syn, mitochondria, and pesticides in PD models

描述(申请人提供)：帕金森病(PD)是一种常见的晚发、进行性神经退行性疾病，其特征是皮质下神经元群体的退化，包括黑质、致密部(SNPC)的多巴胺能神经元，以及由α-突触核蛋白组成的细胞质内含物的存在。虽然帕金森病的病因尚不清楚，但α-突触核蛋白的遗传和生化异常直接参与了帕金森病和其他阿尔法突触核病的发病机制。α-突触核蛋白异常和神经退行性变之间的因果联系被各种遗传模型所显示，其中α-突触核蛋白异常会导致成人起病的神经退行性疾病。一些模型显示了许多人类α-突触核病的特征，包括α-突触核蛋白的异常聚集和皮质下区域的神经变性。我们的研究表明，转基因小鼠的α-突触核病与氧化应激和线粒体异常有关。由于线粒体异常和氧化应激都与帕金森病和其他α-突触核病的发病机制有关，我们将在华星转基因小鼠和细胞模型中研究线粒体功能障碍、氧化应激和α-突触核病之间的病理关系(目标1和2)。此外，我们的研究表明，α-突触核蛋白转基因小鼠对慢性MPTP治疗引起的神经变性的易感性增加。因此，在α-突触核蛋白、环境因素(如杀虫剂)导致的线粒体功能障碍和神经退行性变之间可能存在直接的病理联系。我们将使用已知的抑制复合体I活性的杀虫剂来定义这些因素之间的病理相互作用，这些因素通过细胞培养(AIM 3)和转基因小鼠模型(AIM 4)已知帕金森病的危险因素。这些研究将对与人类阿尔法-突触核病症的发病机制直接相关的过程提供体内实验测试，并可能导致新的治疗方法。 公共卫生相关性：帕金森氏病和相关的阿尔法-突触核病是致命的神经退行性疾病，每年在美国影响约100万人。研究表明，帕金森病与α-突触核蛋白异常、线粒体功能障碍和农药暴露有关。我们将确定内在因素(α-突触核蛋白)和外源性因素(环境毒素)如何在病理上共同作用，影响线粒体功能并导致神经退化。我们的发现将有助于更好地了解帕金森病，并为治疗干预提供新的靶点。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a common late onset, progressive neurodegenerative disease characterized by degeneration of subcortical neuronal populations, including dopaminergic neurons of substantia nigra, pars compacta (SNpc), and presence of the cytoplasmic inclusions composed of alpha-synuclein. While the causes of PD are not known, genetic and biochemical abnormalities of alpha-synuclein are directly implicated in the pathogenesis of PD and other alpha-synucleinopathies. Causal link between alpha-synuclein abnormalities and neurodegeneration is shown by various genetic models where alpha-synuclein abnormalities lead to adult- onset neurological disease with neurodegeneration. Some models exhibit many of the features of human alpha-synucleinopathies, including aberrant aggregation of alpha-synuclein and neurodegeneration in subcortical regions. Our studies indicate that alpha-synucleinopathy in tg mice is associated with oxidative stress and mitochondrial abnormalities. Because both mitochondrial abnormalities and oxidative stress are implicated in the pathogenesis of PD and other a-synucleinopathies, we will examine the pathological relationships between mitochondrial dysfunction, oxidative stress and alpha-synucleinopathies in Hua-Syn Tg mice and in cell models (Aims 1 and 2). In addition, our studies show that alpha-synuclein transgenic mice exhibit increased vulnerability to neurodegeneration induced by the chronic MPTP treatment. Thus, there could be a direct pathologic link between alpha-synuclein, mitochondrial dysfunction via environmental agents (such as pesticides), and neurodegeneration. We will use pesticides that are known to inhibit complex I activity to define the pathological interactions between these factors that known risk factors for PD using cell culture (Aim 3) and transgenic mouse models (Aim 4). These studies will provide in vivo experimental tests of processes that are directly relevant to the pathogenesis of human alpha-synucleinopathies and may lead to new therapeutic approaches. PUBLIC HEALTH RELEVANCE: Parkinson's disease and related alpha-synucleinopathies are fatal neurodegenerative diseases affecting ~1,000,000 individuals annually in US. Studies indicate that PD is associated with alpha-synuclein abnormalities, mitochondrial dysfunction, and pesticide exposure. We will determine how intrinsic (alpha- synuclein) and extrinsic (environmental toxins) factors act in concert of pathologically affect mitochondrial function and lead to neurodegeneration. Our finding will lead to better understanding of PD and new targets for therapeutic intervention.