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The Michael J. Fox Foundation’s Efforts to Develop New Tools for Understanding LRRK2 Biology and the Role of LRRK2 in Parkinson’s Disease Pathology

As the greatest known genetic contributor to Parkinson's disease (PD), the leucine-rich repeat kinase 2 (LRRK2) gene and protein are targets of interest for Parkinson’s disease research and therapeutic development. Unfortunately, critical research tools for understanding the function and role of LRRK2 in disease pathogenesis are lacking. To address this gap, The Michael J. Fox Foundation (MJFF) has taken an active role in designing, validating, and distributing various tools and models that can be used to investigate LRRK2-related mechanisms of PD neurodegeneration or strategies to prevent, slow, or halt disease progression. Here we summarize MJFF-led efforts to develop and characterize a variety of LRRK2-related tools. One such tool is a set of viral vectors that can be used to overexpress wild-type and various mutant forms of LRRK2 in vivo to understand the role of this protein in disease biology, pathways related to PD, and test therapeutic interventions aimed at reducing LRRK2-related pathology. Characterization data for these viral vectors in the rat brain will be presented, including information on the expression profile and resulting neurodegeneration. In addition, we will be presenting data on a new mouse model that overexpresses Rab29 protein—a protein that increases LRRK2 kinase activity and act as a substrate for LRRK2 kinase activity. We will provide data on the protein and mRNA expression levels, as well as data demonstrating the effects on LRRK2 kinase activity. Finally, we will include information on how to access these important tools and models. Ultimately, MJFF’s investment in providing the research community with robust, well-characterized tools and models will speed research towards a cure for PD by enabling research, de-risking investment in PD research, and increasing reproducibility by providing the tools to researchers across labs.

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