RP10: Role of Parkin in regulating GDNF signal transduction and receptor turnover in neurons

RP10：Parkin 在调节神经元 GDNF 信号转导和受体周转中的作用

• 批准号: 174796316
• 负责人: Professor Dr. Edgar Richard Kramer
• 金额: --
• 依托单位: Forschergruppe Entwicklung und Erhaltung des Nervensystems (aufgelöst)
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/174796316?language=en
• 关键词: RP10; Role; Parkin; regulating; GDNF

Mutations in the ubiquitin protein ligase parkin can cause Parkinson s disease (PD) by altering protein turnover. Parkin polyublquitylates some substrates to mark them for degradation by the proteasome and others, such as Eps15, are monoubiquitylated. Monoubiquitylated Eps15 can not bind to cell surface receptors and trigger clathrindependent endocyotsis, thereby enhancing receptor signaling.Work from my laboratory suggests that parkin and Eps15 also regulate the protein turnover of the glial cell line-derived neurotrophic factor (GDNF) receptor Ret in neurons. We found that Ret can bind to Eps15 and parkin; parkin alters the internalization of GDNF; and the amount of Ret protein seems to be reduced in parkin-deficient mice.In this project, we will investigate how parkin, Eps15 and Ret interact; how this interaction is regulated; and how parkin influences the internalization, degradation and signaling of Ret in neurons by performing biochemical and cell culture experiments. In addition, we will study the physiological relevance of this interaction in double transgenic parkin and Ret mice and by analyzing brain tissue from PD patients with mutations in parkin. These data will allow Integrating Ret in the protein network altered in PD patients and will enhance our understanding of this complex disease.

泛素蛋白连接酶帕金的突变可以通过改变蛋白质周转而引起帕金森病（PD）。Parkin polyubiquitylates一些底物，以标记它们被蛋白酶体降解，而其他底物，如Eps 15，则被单泛素化。单泛素化的Eps 15不能与细胞表面受体结合并触发非网格依赖性内吞作用，从而增强受体信号传导。本实验室的工作表明，parkin和Eps 15还调节神经元中胶质细胞系源性神经营养因子（GDNF）受体Ret的蛋白质周转。我们发现Ret可以与Eps 15和parkin结合; parkin改变GDNF的内化;并且在parkin缺陷的小鼠中Ret蛋白的量似乎减少。在本项目中，我们将通过进行生化和细胞培养实验来研究parkin，Eps 15和Ret如何相互作用;这种相互作用是如何调节的;以及parkin如何影响神经元中Ret的内化，降解和信号传导。此外，我们将研究这种相互作用在双转基因parkin和Ret小鼠中的生理相关性，并通过分析帕金森病患者的脑组织与parkin突变。这些数据将允许将Ret整合到PD患者改变的蛋白质网络中，并将增强我们对这种复杂疾病的了解。