Do Ariadne and Parkin Share Redundant Function

BB PrincipInavlestigator/PDroirgerca（tLomar .ctirte，t，raiadle）：Schwartz，LM.说明：说明申请的广泛、长期目标和具体目标，并参考项目的健康相关性。简要描述研究设计和实现这些目标的方法。避免总结过去的成就和使用第一人称。本说明书旨在作为与本申请分开的拟议工作的简洁和准确的描述。如果申请获得资助，这种帕金森病（PD）是美国第二常见的神经退行性疾病。最近，几个患有常染色体隐性青少年帕金森氏症（AR-JP）的家庭被证明携带一种名为Parkin的基因突变，该基因是一种遍在蛋白E3连接酶。 NINDS最近将Parkin和相关蛋白确定为深入研究的目标（RFA NS- 01-005）。在这个建议中，我们专注于阿里阿德涅，最接近帕金已知的结构同源物。Ariadne是一种特征性很差的蛋白质，具有与Parkin相似的整体结构组织。阿里阿德涅和帕金都与相同的泛素E2酶结合，在果蝇中，阿里阿德涅的缺失导致生存能力降低和静息震颤。在初步研究中，我们已经证明了Ariadne和Parkin具有重要的结构和功能特性。在本研究中，我们将使用生物化学、分子、细胞和遗传学方法来验证Ariadne和Parkin是：1）结构和功能同源物; 2）参与Lewy小体形成; 3）保护细胞免受体外和体内有害刺激的假设。 这项工作可以使我们：1）解释为什么帕金的整体功能丧失突变的表型效应主要限于多巴胺能神经元; 2）验证路易体样细胞质内含物反映了细胞的适应性反应; 3）提供对这类蛋白质功能的深入了解，这可以增强我们对帕金功能的理解。这样的描述将成为公开信息。因此，不包括专有/机密信息。不要超过所提供的8步。性能现场=

BB PrincipInavlestigator/PDroirgerca(tLomar .ctirte,t, raiadle): Schwartz, LM. DESCRIPTION: State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project. Describe concisely the research design and methods for achieving these goals. Avoid summaries of past accomplishments and the use of the first person. This description is meant to serve as a succinct and accurate descdpti0n of the proposed work when separated from the application. If the application is funded, this Parkinson's Disease (PD) is the second most common neurodegenerative disorder in the United States. Recently, several families with Autosomal Recessive Juvenile Parkinsonism (AR-JP) have been demonstrated to carry mutations in a gene termed Parkin, a ubiquitin E3 ligase. NINDS recently identified Parkin and related proteins as targets for intensive investigation (RFA NS- 01-005). In this proposal, we focus on Ariadne, the closest known structural homolog of Parkin. Ariadne is a poorly characterized protein with a similar overall structural organization to Parkin. Both Ariadne and Parkin bind to the same ubiquitin E2 enzymes and in Drosophila, loss of Ariadne results in reduced viability and resting tremors. In preliminary studies, we have demonstrated that Ariadne and Parkin share significant structural and ftmetional properties In this proposal, we will use biochemical, molecular, cellular and genetic methods to test the hypotheses that Ariadne and Parkin are: 1) structural and functional homologs; 2) participate in Lewy Body formation; and 3) protect cells both in vitro and in vivo from noxious stimuli. This work may allow us to: 1) explain why the phenotypic effects of global loss-of-function mutations in Parkin are largely restricted to dopaminergic neurons; 2) verify that Lewy Body-like cytoplasmic inclusions reflect an adaptive response by cells; and 3 provide insight into the functioning of this class of proteins which can enhance our understanding of Parkin function in cells. description, as is, will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED THE 8PACE PROVIDED. PERFORMANCE SITE ========================================Section End===========================================