Influence of genetic variation on manganese neurotoxicity and Parkinson's disease

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DESCRIPTION (provided by applicant) The candidate's research goals are to investigate manganese (Mn)-induced transport and neurotoxicity in the context of environmental exposure and pathogenesis of neurodegeneration. Parkinson's disease is a neurodegenerative disorder affecting four million people worldwide, including one million people in North America. Chronic exposure to Mn results in neurobehavioral deficits similar to Parkinson's disease. Mn accumulation in the brain is a known risk factor for Parkinson's disease. Despite growing awareness of the problems associated with Mn exposure, little is known about the underlying mechanisms. Accumulating evidence from in vitro studies suggests that ferroportin (Fpn), a known iron exporter, plays a role in Mn transport. The candidate's preliminary studies directly support this model. She found that flatiron mice, which are deficient in Fpn, have lower intestinal absorption and reduced biliary excretion of Mn. Her in vitro exogenous expression studies show that wild-type Fpn prevents Mn accumulation and cytotoxicity while the flatiron mutation Fpn (H32R) completely abrogates this cytoprotective effect. However, how Fpn deficiency influences neurotoxicity and neurodegeneration is not understood. Based on the investigators' in vitro and animal model studies, the candidate hypothesize that loss of Fpn function enhances brain Mn accumulation leading to Mn neurotoxicity. Known human mutations in Fpn cause ferroportin disease, an inherited form of hemochromatosis. A corollary to the candidate's hypothesis is that individuals with Fpn mutations are more vulnerable to neurotoxicity and neurodegenerative diseases associated with Mn exposure. To test these hypotheses, the candidate will combine the use of dopaminergic SH-SY5Y cells, flatiron mice, and human subjects with Parkinson's disease. During the K99 mentored phase, under the mentorship of Dr. Wessling-Resnick at Harvard School of Public Health, the candidate will test the major hypothesis that Fpn functions as a Mn transporter in the brain and that loss of Fpn function enhances brain Mn accumulation and neurotoxicity. The Mentored Phase will provide training and establish the experimental foundation to explore the human consequences of this hypothesis during the Independent Phase. The specific aims are: 1) To examine the role of Fpn in brain Mn transport in vivo. 2) To characterize Mn neurotoxicity in flatiron mice after exposure. The candidate's long-term career goal is to obtain a tenure- track faculty position at an academic institution where she will be abl to expand her area of research, train and instruct graduate and undergraduate students, and collaborate with and learn from her academic peers. Utilizing the training and results obtained during the mentored phase, she will test the hypothesis that Fpn deficiency enhances Mn neurotoxicity such that individuals with mutations in Fpn are more vulnerable to neurodegenerative diseases. The specific aims are: 3) To determine the effects of known human Fpn mutations on Mn neurotoxicity in vitro. 4) To explore the associations between Fpn gene variants and Parkinson's disease.