Mechanisms of Brain Manganese Homeostasis and Manganese-induced Parkinsonism

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PROJECT SUMMARY Manganese (Mn) is an essential metal required for normal neural development and function; however, at elevated levels, it is neurotoxic. Adults and children exposed to Mn through environmental or occupational sources exhibit incurable motor and cognitive deficits. Mn overexposure is also associated with a-synuclein aggregation and increased risk for developing Parkinson’s Disease. Mn presents an environmental health concern, but the mechanisms of brain Mn homeostasis and the effects of Mn on brain function remain are not fully understood. Upon overexposure, Mn builds up in the basal ganglia; however, the specific neuronal targets of Mn are unclear. A major question in the field is whether Mn primarily effects catecholaminergic, particularly dopaminergic, or GABAergic neurons in the basal ganglia. The proposed study aims to address this question by selectively increasing Mn in catecholaminergic and GABAergic neurons which was not previously possible. Homozygous mutations in the Mn efflux transporter, SLC30A10, resulted in increased brain Mn and Mn-induced parkinsonism. The current proposal leverages the discovery of SLC30A10 to understand the mechanisms of brain Mn homeostasis and the effects of increased Mn in all or some neurons. Using full-body, pan/neuronal/glial, liver-, and endoderm-specific Slc30a10 knockout mice, we discovered that under basal conditions, brain Mn levels are primarily regulated by activity of SLC30A10 in the digestive system, while its activity in the brain protected against neurotoxicity during Mn overexposure. This work established the predominance of SLC30A10 in regulating brain Mn levels and presented a novel method for studying Mn neurotoxicity. Subsequent work will use pan-neuronal/glial, catecholaminergic, and GABAergic Slc30a10 knockouts to selectively increase Mn in all, catecholaminergic, or GABAergic neurons. This study will test the hypothesis that catecholaminergic, but not GABAergic, Slc30a10 knockouts mimic the phenotype observed in pan-neuronal/glial knockouts. Proposed experiments will assay for Mn-induced changes in motor function, neurodegeneration, neurotransmission, and gene expression under normal conditions and during an oral Mn exposure relevant to human disease. The proposed study uses a multidisciplinary approach to further elucidate how brain Mn homeostasis is regulated and how excess brain Mn impacts the catecholaminergic and GABAergic systems. Proposed studies will be performed under the supervision of sponsor, Dr. Somshuvra Mukhopadhyay and co-sponsor, Dr. Robert Messing at the University of Texas at Austin (UT Austin). Dr. Mukhopadhyay is an expert in Mn toxicology, and Dr. Messing has a well-established career in neuroscience. Their combined expertise and the collaborative environment at UT Austin are critical for the successful completion of the proposed study and for providing the training and mentorship necessary for the applicant’s goals of a career in academia and neuroscience research.