NEUROPATHOLOGY OF CHRONIC MANGANESE EXPOSURE

描述（由申请人提供）：帕金森病（PD）是一种常见的神经退行性疾病，在北美影响超过100万人。PD的原因在大多数情况下是未知的，但环境金属暴露可能是一个危险因素。这项研究的主要目的是比较南非锰（Mn）矿工和南非金（Au）矿工的大脑，以研究长期暴露于Mn的工人会出现早期PD典型神经病理学结果的假设，进一步阐明环境金属暴露在PD发病机制中的作用。为了实现这一目标，我们将进行神经病理学检查的大脑从南非锰矿工和南非Au矿工的参考大脑。在以下固定脑区域中，使用NeuN、GFAP和CD 68抗体进行免疫组织化学染色后，使用体视学对神经元、星形胶质细胞和小胶质细胞进行计数：苍白球内侧、黑质内侧部、蓝斑和嗅球。我们还将尝试将体视学细胞计数与每个感兴趣区域的组织锰沉积相关联。组织用抗α-突触核蛋白抗体染色后，还将评价路易体、路易神经突和α-突触核蛋白聚集体（如果有的话）的分布。此外，神经元的数量和神经胶质增生的程度或其他标志物的损伤矿工暴露于锰将与重建的职业锰暴露，以及与帕金森氏症的临床症状，从过去的神经系统检查可通过就业健康档案。将在这些相同的脑区域中用蛋白质印迹定量α-突触核蛋白及其聚集体的量。此外，残留的酪氨酸羟化酶（TH）将被确定在纹状体的矿工。我们将尝试关联α-突触核蛋白聚集和残留的纹状体TH锰矿工重建职业锰暴露以及帕金森氏症的临床症状，从现有的就业健康档案。该项目涉及美国PD和Mn研究人员与世界领先的Mn生产国南非国家职业健康研究所的独特国际合作。公共卫生相关性：这项研究的结果将更好地了解金属暴露，特别是锰和帕金森病之间的关系。这项研究的结果可能会转化为预防措施，以减少帕金森病的发生率。

DESCRIPTION (provided by applicant): Parkinson disease (PD) is a common neurodegenerative disorder affecting more than 1 million people in North America. The cause of PD is unknown in most cases but environmental metal exposure may be a risk factor. The primary goal of this grant is to compare brains of South African manganese (Mn) miners to the brains of South African gold (Au) miners to investigate the hypothesis that workers with chronic exposure to Mn will have neuropathologic findings typical of early PD, to further clarify the role of environmental metal exposure in the pathogenesis of PD. To accomplish this goal, we will perform neuropathologic examinations of brains obtained from South African Mn miners and reference brains from South African Au miners. Neurons, astrocytes and microglia will be counted with stereology, following immunohistochemical staining with antibodies against NeuN, GFAP and CD68, in the following fixed brain regions: globus pallidus interna, substantia nigra pars compacta, locus ceruleus, and olfactory bulb. We will also attempt to correlate sterologic cell count with tissue Mn deposition in each region of interest. Distribution of Lewy bodies, Lewy neurites and alpha-synuclein aggregates, if any, will also be evaluated after tissues are stained with an antibody against alpha-synuclein. In addition, the number of neurons and the extent of gliosis or other markers of injury in miners exposed to Mn will be correlated with the reconstructed occupational Mn exposure as well as with clinical signs of parkinsonism from past neurological exams available through employment health files. The amount of alpha-synuclein and its aggregates will be quantified with Western blot in these same brain regions. Additionally, residual tyrosine hydroxylase (TH) will be determined in the striatum of miners. We will attempt to correlate alpha-synuclein aggregation and residual striatal TH in Mn miners with reconstructed occupational Mn exposure as well as clinical signs of parkinsonism from available employment health files. This project involves a unique international collaboration of American PD and Mn researchers and the South African National Institute of Occupational Health in the world's leading Mn producing country. PUBLIC HEALTH RELEVANCE: The results of this study will provide a better understanding of the relationship between metal exposure, specifically, manganese and Parkinson disease. Findings from this study may be translated into preventative measures to reduce the frequency of Parkinson disease.