Using BAC Transgenic Mice to Determine Causative Role of LRRK2 Kinase Activity in PD Pathogenesis
Critical Challenges in PD: Translating Genetic Findings Into, 2007
Emerging evidence has implicated kinase activity of LRRK2, the PD. The objective of this project is to use novel animal models to determine whether enhanced LRRK2 kinase activity is causative to the pathological process of PD. Study of these models harboring various LRRK2 mutations would allow effective evaluation of the relevance of LRRK2 kinase activity to the disease onset and development.
We hypothesize that LRRK2 kinase activity and cellular functions are specifically regulated in the brain, and that the distinct level and regulation of brain LRRK2 kinase activity are important for the disease development in PD. To test these hypotheses, we have used a novel mouse transgenic approach (BAC transgenic) and established a series of transgenic pre-clinical models expressing LRRK2 variant proteins, such as PD-associated mutant and kinase-dead mutant. We will investigate potential PD-related pathology and behavioral characteristics in these LRRK2 transgenic mice. In addition, we will purify LRRK2 variant proteins from transgenic brains, and analyze their relative kinase activity.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
We anticipate that our study not only will gain insight into the pathogenic mechanism of PD, but also will provide important information as well as experimental reagents in evaluating LRRK2 kinase as drug target for the treatment of PD. Depending on the outcome of the study, the result is expected to provide future direction of LRRK2 research, which should yield critical information regarding pathogenic pathway of PD and development of better diagnosis/treatment for PD.
The result is expected to show whether expression of PD-associated mutant of LRRK2 leads to PD-like pathology, and whether occurrence of PD-like process requires LRRK2 kinase activity in the pre-clinical models. If expression of LRRK2 kinase-dead mutant abolishes the pathogenic effect of LRRK2 in transgenic mice, it will strongly indicate LRRK2 kinase activity as a culprit. Otherwise, LRRK2 kinase may be irrelevant to the PD-like pathology and other properties of LRRK2 should be assessed for the involvement in the disease progression.
Professor of Neurology and Neuroscience, Director of Basic and Translational Research of Movement Disorders at Icahn School of Medicine at Mount Sinai
Location: New York, New York, United States