Role of Parkin in Familial and Idiopathic Parkinson's Disease

帕金森病（Parkinson's disease，PD）是一种进行性神经退行性疾病，其特征在于运动性和非运动性帕金森病（Parkinson's disease，PD）。 运动障碍虽然这种疾病的病因尚不清楚，但基因突变是导致这种疾病的原因。 对于家族性PD可能提供关键的分子见解的基础机制，特发性 疾病泛素E3连接酶parkin的功能缺失突变是常染色体显性遗传最常见的原因。 隐性PD帕金现在被广泛认为是一种具有广泛影响的促生存蛋白 在线粒体生物学以及其他领域的研究对这些功能的更全面理解将导致 更深入地了解PD的神经退行性过程，以及新途径的识别 可以作为疾病改良的目标。我们工作的长期目标是揭示 负责帕金在神经元中的保护作用的机制。我们认为，细胞质和 脑内定位的帕金池在维持健康的神经元中起着重要作用。这 本申请将探索胞质帕金蛋白在人神经元中的神经保护功能中的作用。使用 工程化的等基因的和基于患者的WT和parkin无效多能干细胞分化为人 神经元的命运，我们将揭示激活帕金细胞质池的条件。我们将确定 控制parkin激活的上游蛋白质及其对人类神经元细胞死亡的保护。然后， 我们将探讨BH3结构域在识别一个不断扩大的推定底物类中的作用， 细胞质parkin E3连接酶活性。调节神经元parkin功能的途径可能会揭示 治疗干预的创新目标，以上调parkin活性并诱导神经保护， 神经系统疾病

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by both motor and non- motor disturbances. While the etiology of the disease is unknown, genetic mutations responsible for familial forms of PD likely provide critical molecular insights into the underlying mechanisms of idiopathic disease. Loss-of-function mutations in the ubiquitin E3 ligase parkin are the most common cause of autosomal recessive PD. Parkin is now widely recognized as a pro-survival protein that possesses broad ranging effects on mitochondrial biology, and beyond. A more complete comprehension of these functions will will lead to a firmer understanding of the neurodegenerative process in PD, as well as the identification of new pathways that may be targeted for disease modification. The long-term goal of our work is to uncover the molecular machinery responsible for parkin's protective effects in neurons. We propose that both the cytosolic and mitochondrial-localized pools of parkin play important roles in the maintenance of healthy neurons. This application will explore the role of cytosolic parkin in its neuro-protective function in human neurons. Using engineered isogenic and patient based WT and parkin null pluripotent stem cells differentiated to human neuronal fates, we will uncover the conditions that activate the cytoplasmic pool of parkin. We will identify the upstream proteins that control parkin activation and its protection against cell death in human neurons. Then, we will explore the role of BH3 domains in the recognition of an expanding class of putative substrates of cytoplasmic parkin E3 ligase activity. The pathways found to regulate neuronal parkin function may shed light on innovative targets for therapeutic intervention to up-regulate parkin activity and induce neuro-protection in neurologic disease.