Mechanisms of Brain Manganese Homeostasis and Manganese-induced Parkinsonism

项目摘要 锰（Mn）是正常神经发育和功能所需的必需金属;然而， 在高浓度下，它具有神经毒性。成人和儿童通过环境或职业接触锰 来源表现出无法治愈的运动和认知缺陷。Mn过表达也与α-突触核蛋白有关 聚集和增加患帕金森病的风险。Mn代表环境健康 关注，但脑锰稳态的机制和锰对脑功能的影响仍然没有 完全理解在过度暴露时，Mn在基底神经节中积聚;然而，特定的神经元靶点 Mn不清楚。该领域的一个主要问题是Mn是否主要影响儿茶酚胺能，特别是 基底神经节中的多巴胺能或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Mn，这在以前是不可能的。 Mn外排转运蛋白SLC 30 A10的纯合突变导致脑Mn和 锰诱发的帕金森症目前的建议利用SLC 30 A10的发现来了解 脑锰稳态的机制和所有或一些神经元中锰增加的影响。使用全身， 我们在全/神经元/神经胶质、肝脏和内胚层特异性Slc 30 a10敲除小鼠中发现，在基础 在某些条件下，脑Mn水平主要由消化系统中的SLC 30 A10活性调节，而其 在Mn过量期间，脑中的活性保护免受神经毒性。这项工作建立了 SLC 30 A10在调节脑锰水平中的优势，并提出了一种研究锰的新方法 神经毒性后续工作将使用泛神经元/神经胶质、儿茶酚胺能和GABA能Slc 30 a10 敲除以选择性地增加所有、儿茶酚胺能或GABA能神经元中的Mn。这项研究将测试 假设儿茶酚胺能，但不是GABA能，Slc 30 a10敲除模拟在 泛神经元/神经胶质敲除。拟议的实验将测定锰诱导的运动功能变化， 在正常条件下和口服锰期间， 与人类疾病有关的暴露。这项拟议中的研究采用多学科方法进一步阐明 如何调节脑锰稳态以及过量的脑锰如何影响儿茶酚胺能和 GABA能系统。拟定研究将在申办者Somshuvra博士的监督下进行 Mukhopadhyay和共同发起人，得克萨斯大学奥斯汀分校（UT奥斯汀）的罗伯特·梅辛博士。博士 Mukhopadhyay是锰毒理学方面的专家，而Messing博士在神经科学方面有着良好的职业生涯。 他们的综合专业知识和UT奥斯汀的协作环境是成功的关键 完成拟议的研究，并为申请人提供必要的培训和指导， 学术界和神经科学研究的职业目标。

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.