The cause of Parkinson's in most patients is unknown, but in a small percentage of cases (three to five percent), mutation in a specific gene is causal. Several genes have been conclusively linked to PD such as alpha-synuclein, parkin, DJ-1, PINK1, and most recently LRRK2. LRRK2 is of particular interest as mutations in this gene account for a relatively large percentage of PD cases and show hallmark dopaminergic degeneration as well as relevant protein aggregation. Our lab will generate (1) a knock-in pre-clinical model in which a common mutation in LRRK2 (R1441C) has been introduced into the mouse genome and (2) several transgenic mouse lines in which either wild-type or R1441C human LRRK2 is overexpressed. We will analyze these mice to better understand how neurodegeneration and disease progression occurs. Development of appropriate animal models for PD is critical for the identification of potential targets for the treatment and prevention of PD.
Final Outcome
Dr. Shen successfully generated LRRK2 knock-in mice. These mice showed no evidence of dopaminergic degeneration nor of alpha-synuclein aggregation. However, there was evidence of alterations in dopamine metabolism. The mice that Dr. Shen generated have been deposited in the Jackson Laborotories for distribution to the broader research community.
Results of this work were published in the journal Proceedings of the National Academy of Sciences.