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，影响北美超过100万人。在大多数情况下，PD的病因尚不清楚，但环境金属暴露可能是一个危险因素。这项资助的主要目的是比较南非锰（Mn）矿工和南非金（Au）矿工的大脑，以研究长期接触锰的工人会有早期帕金森病典型的神经病理表现的假设，进一步阐明环境金属暴露在帕金森病发病机制中的作用。为了实现这一目标，我们将对来自南非锰矿矿工的大脑和来自南非金矿矿工的参考大脑进行神经病理学检查。通过免疫组化NeuN、GFAP和CD68抗体染色，在以下固定脑区：苍白球内、黑质紧实部、蓝斑和嗅球，用体视术计数神经元、星形胶质细胞和小胶质细胞。我们也将尝试关联体细胞计数与组织锰沉积在每个感兴趣的区域。如果有路易小体、路易神经突和α -突触核蛋白聚集体的分布，也将在组织被α -突触核蛋白抗体染色后进行评估。此外，暴露于锰的矿工的神经元数量和神经胶质瘤或其他损伤标志物的程度将与重建的职业锰暴露以及通过就业健康档案获得的过去神经学检查中帕金森病的临床症状相关。α -突触核蛋白及其聚集体的数量将在这些相同的大脑区域用Western blot进行量化。此外，还将测定矿工纹状体中残留的酪氨酸羟化酶（TH）。我们将尝试将α -突触核蛋白聚集和残余纹状体TH与重建的职业锰暴露以及可获得的就业健康档案中的帕金森病临床症状联系起来。该项目涉及美国PD和Mn研究人员与世界主要Mn生产国南非国家职业卫生研究所的独特国际合作。公共卫生相关性：本研究的结果将更好地了解金属暴露，特别是锰与帕金森病之间的关系。这项研究的结果可能转化为预防措施，以减少帕金森病的频率。

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.