Mutations in LRRK2 are the most common cause of autosomal dominant Parkinson's disease (PD), and predispose to sporadic PD as well. Some patients with LRRK2 mutations and PD manifest neuropathologically as tauopathies, with deposition of abnormally aggregated tau in affected brain regions. We have been thus motivated to explore the interaction of LRRK and tau using our Drosophila model of tauopathy. We find that either decreasing or increasing levels of the fly homolog of LRRK2, Lrrk, enhances tau neurotoxicity. In our proposed studies we will now test the specific hypothesis that Lrrk enhances tau neurotoxicity by abnormally stabilizing actin. We further posit that increased levels of F-actin then promote mislocalization of the critical mitochondrial fission protein Drp1 and result in mitochondrial morphological changes and increased oxidative stress, as we have previously demonstrated in our tauopathy model. We also propose, based on our preliminary data, that LRRK2- associated neurodegeneration reflects loss of LRRK function, through a dominant negative effect in the case of dominant human mutations. We will also test this hypothesis in our Drosophila model. In a final series of experiments to validate our hypotheses, we will examine F-actin levels, Drp1 localization and mitochondrial pathology in mice expressing human tau in the context of wild type or mutant human LRRK2. All together these experiments are expected to define an important functional role for LRRK2 in controlling the actin cytoskeleton and to define the mechanism of PD-related LRRK2 mutations. In concert with these important scientific goals, the research plan will provide strong training in genetics, cell biology and neuropathology for the fellowship candidate, Dr. Farah Bardai.

Public Health Relevance

Mutations in LRRK2 are the most common cause of Parkinson's disease. Here we will explore a novel link between LRRK2 and tau, another protein implicated in distinct disorders of abnormal movements. Our studies will explore the normal function of LRRK2, and will increase our understanding of the pathogenic pathways leading to Parkinson's disease and related disorders.

National Institute of Health (NIH)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Sieber, Beth-Anne
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Brigham and Women's Hospital
United States
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