Understanding the role of LRRK2 in protein translation - implications for Parkinson's disease.

• Main Author: Cheng, Yue Xiang.
• Other Authors: School of Biological Sciences
• Format: Final Year Project
• Language: English
• Published: 2010
• Subjects: DRNTU::Science::Biological sciences::Human anatomy and physiology::Neurobiology
• Online Access: http://hdl.handle.net/10356/39552
• Institution: Nanyang Technological University

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder affecting millions of elderly worldwide. Although most cases of PD are idiopathic, a small proportion is caused by genetic mutations. Among these, mutations in Leucine Rich Repeat Kinase 2 (LRRK2) have been shown to be the most prevalent cause of familial PD, with the G2019S variant being the most common. Several groups have demonstrated that mutations in LRRK2 increase its kinase activity and result in neurotoxicity. One of the few substrates of LRRK2 that has been identified to date is 4E-BP, a regulator of protein translation. When 4E-BP is phosphorylated, it initiates CAP-dependent protein translation that drives the expression of many proteins including cyclin D1. Kinase activating mutations of LRRK2 lead to hyperphosphorylation of 4E-BP and thereby de-regulated protein translation. In my current study, I have exploited this property of LRRK2 and created a cyclin D1 5’ UTR-based reporter assay to measure LRRK2-induced protein translation. Using this system as a basis for drug screening, I found that EGCG, a green tea-derived catechin, mitigates LRRK2 G2019S-mediated enhancement of protein translation by reducing the levels of p4E-BP. My results provided proof-of-concept that the reporter system that I have developed would be useful for drug screening. Notably, a parallel study done in my supervisor’s laboratory has confirmed the neuroprotective effects of EGCG against LRRK2-induced neurotoxicity in vivo. Taken together, I have demonstrated here the successful development of a screening tool for compounds of potential therapeutic value to LRRK2-related PD patients.