Mechanisms of Brain Manganese Homeostasis and Manganese-induced Parkinsonism

项目总结 锰是正常神经发育和功能所必需的一种金属；然而， 当水平升高时，它具有神经毒性。通过环境或职业接触锰的成人和儿童 病源表现出无法治愈的运动和认知缺陷。锰过量暴露也与α-突触核蛋白有关 聚集和患帕金森氏症的风险增加。锰代表着一种环境健康 但有关脑内锰稳态的机制以及锰对脑功能的影响尚不清楚。 完全理解。过度暴露后，锰在基底节积聚；然而，特定的神经元靶点 锰的含量还不清楚。该领域的一个主要问题是，锰是否主要影响儿茶酚胺能，特别是 基底节中的多巴胺能或GABA能神经元。拟议的研究旨在解决这一问题。 通过选择性地增加儿茶酚胺能和GABA能神经元中的锰，这在以前是不可能的。 锰外流转运蛋白SLC30A10的纯合子突变导致脑内锰含量增加和 锰诱导的帕金森氏症。当前的提案利用SLC30A10的发现来理解 脑内锰稳态的机制及全部或部分神经元增加锰的影响。使用全身， PAN/神经元/神经胶质细胞、肝脏和内胚层特异的Slc30a10基因敲除小鼠，我们发现在基础 在这种情况下，大脑中的锰水平主要由消化系统中SLC30A10的活性来调节，而其 在锰过量暴露时，大脑中的活动可防止神经毒性。这项工作奠定了 SLC30A10在调节脑内锰水平方面的优势，为研究锰提供了一种新方法 神经毒性。后续工作将使用泛神经元/神经胶质细胞、儿茶酚胺能和GABA能SLc30a10 基因敲除选择性地增加ALL、儿茶酚胺能或GABA能神经元中的锰。这项研究将测试 假设儿茶酚胺能，而不是GABA能，Slc30a10基因敲除模仿在 泛神经元/神经胶质细胞敲除。拟议中的实验将检测锰诱导的运动功能变化， 正常情况下和口服过程中的神经退变、神经传递和基因表达 与人类疾病有关的暴露。拟议的研究使用多学科方法来进一步阐明 脑内锰稳态是如何调节的，脑内过量的锰是如何影响儿茶酚胺能和 GABA能系统。拟议的研究将在赞助商SomShuvra博士的监督下进行 MukHopadhyay和共同赞助人，德克萨斯大学奥斯汀分校的罗伯特·梅辛博士。Dr。 MukHopadhyay是锰毒理学专家，梅辛博士在神经科学方面有很好的职业生涯。 他们的专业知识和得克萨斯大学奥斯汀分校的协作环境是成功 完成拟议的研究，并为申请人提供必要的培训和指导 在学术界和神经科学研究领域的职业目标。

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.