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Investigating Defects in Mitochondrial Functions, Transport, Fusion/Fission in LRRK2 Pre-clinical Models

This grant builds upon the research from a prior grant: Park8 Pre-clinical Models and LRRK2 Kinase Substrates

The study of genetic forms of Parkinson’s disease is important for revealing the mechanisms of pathogenesis, and for future therapeutic developments. LRRK2 is the recently identified gene for Park8-autosomal dominant Parkinson’s disease. Mutations in LRRK2 have the highest prevalence in familial PD. We used our novel method of Bacterial Artificial Chromosome (BAC) mediated transgenesis and successfully generated pre-clinical models for LRRK2. These pre-clinical models are being used to investigate what cellular dysfunctions are caused by mutations in Lrrk2.   Mitochondrial dysfunction is implicated in normal aging and neurodegenerative diseases including Alzheimer’s, Huntington’s and Parkinson’s diseases. We and others demonstrated that four familial PD gene products are either physically localized to mitochondria (PINK1, DJ-1 and LRRK2), or lead to a functional deficit in mitochondria (Parkin, DJ-1), suggesting an important role of mitochondria in PD pathogenesis. In addition to the functions inside mitochondria, defects in mitochondrial transport, fission/fusion have been implicated in apoptosis, neurodegeneration and aging. Intriguingly, proteins in the mitochondrial transport, fission/fusion machinery share conserved functional domains with LRRK2. Therefore, in this proposed study, we will investigate mitochondrial functions, transport and fusion/fission in LRRK2 transgenic mice. 

Final Outcome

Dr. Li continues to characterize the behavioral and neuropathological characteristics of his LRRK2 BAC transgenic mice. Investigations into mitochondrial function also continue.


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