Parkin is ubiquitinated by Nrdp1 and abrogates Nrdp1-induced oxidative stress

• Published in: Neuroscience letters Vol. 440; no. 1; pp. 4 - 8
• Main Authors: Yu, Furong, Zhou, Jianhua
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 25.07.2008; Elsevier
• Subjects: Biological and medical sciences; Cell Line; Dose-Response Relationship, Drug; E3 ligase; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; Humans; Immunoprecipitation - methods; Mutation - physiology; Nrdp1; Oxidative Stress - drug effects; Oxidative Stress - physiology; Parkin; Reactive oxidative stress; Reactive Oxygen Species - metabolism; RNA, Small Interfering - pharmacology; Transfection - methods; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitin-Protein Ligases - pharmacology; Ubiquitin-Protein Ligases - physiology; Ubiquitination; Ubiquitination - physiology; Vertebrates: nervous system and sense organs; Nrdp1; Ubiquitination; E3 ligase; Reactive oxidative stress; Parkin; Oxidative stress; Enzyme; Ligases
• ISSN: 0304-3940; 1872-7972
• DOI: 10.1016/j.neulet.2008.05.052

Parkin plays an important role in the pathogenesis of Parkinson's disease. We previously described that Nrdp1, a RING-finger ubiquitin E3 ligase, interacted with Parkin by the yeast two-hybrid assay and by co-immunoprecipitation. Here we further demonstrated that overexpression of Nrdp1 significantly reduced the endogenous Parkin level in an Nrdp1 dosage-dependent and proteasome-dependent manner. More importantly, Nrdp1 ubiquitinated Parkin and catalyzed the poly-ubiquitin chains on Parkin in vitro as well as in cells, indicating Parkin is an Nrdp1 substrate. In addition, we demonstrated that overexpression of Nrdp1 increased the production of reactive oxygen species (ROS), which was abrogated by co-expression of Parkin. Conversely, suppression of Nrdp1 by shRNA conferred SH-SY5Y cells a lower ROS level. Together, we provided evidence that interactions between Nrdp1 and Parkin negatively regulated Parkin level and affected ROS production, suggesting that Nrdp1 may play a role in Parkinson's disease.