DJ-1 and its interactions with Parkin and Alpha-Synuclein

描述（由申请人提供）：帕金森病（PD）是最常见的神经退行性运动障碍，影响1-4%的65岁以上人群。迄今为止，大多数PD患者的病因尚不清楚，涉及的细胞通路也不明确。PD诊断的风险随着年龄的增长而增加。因此，随着人口的日益老龄化，有必要更好地了解PD的发病机制。由于遗传缺陷，缺乏一种名为DJ-1的蛋白质会导致一些患者患上帕金森病。该项目的总体目标是确定DJ-1的细胞作用及其与其他蛋白质，Parkin和α-Synuclein的关系，这些蛋白质也直接涉及帕金森病。在该提案中，将评估DJ-1调节帕金表达的能力和该过程中涉及的机制。将研究DJ-1的生物学活性和由于致病突变而导致的生物学活性丧失的影响。还提出将鉴定DJ-1的新修饰，因为它们可以提供对DJ-1功能的见解。还将在体内评估DJ-1抑制α-突触核蛋白聚集的能力，所述α-突触核蛋白聚集参与帕金森病的病理生物学。这些研究将通过使用细胞培养系统和人类疾病的转基因小鼠模型进行。这些研究的完成将使我们更好地了解DJ-1的生物学功能及其与其他特定蛋白质（如Parkin和α-Synuclein）的相互作用，以确定PD病理生物学中涉及的生物学途径。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is the most common neurodegenerative movement disorder, affecting 1-4% of the population above the age of 65. To date, the cause for the majority of patients with PD is unknown and the cellular pathways implicated are ill-defined. The risk for PD diagnosis increases with age. Thus, with an increasingly aging population, it becomes necessary to better understand PD pathogenesis. Due to genetic defects, a paucity of a protein called DJ-1 can lead to Parkinson's disease in some patients. The overall goal of the project is to identify the cellular role(s) of DJ-1 and its relationships to other proteins, Parkin and alpha-Synuclein, which are also directly implicated in Parkinson's disease. In this proposal, the ability of DJ-1 to regulate Parkin expression and the mechanism(s) involved in the process will be assessed. The biological activities of DJ-1 and effects of the loss thereof due to disease-causing mutations will be investigated. It also is proposed that novel modifications of DJ-1 will be identified, as they may provide insights into the function of DJ-1. The ability of DJ-1 to suppress alpha-Synuclein aggregation, which is involved in pathobiology of Parkinson's disease, will also be assessed in vivo. These studies will be conducted by using cell culture systems and transgenic mouse models of the human disease. The completion of these studies will provide a better understanding of the biological function of DJ-1 and its interplay with other specific proteins such as Parkin and alpha-Synuclein in defining biological pathways involved in the pathobiology of PD.