NEUROPATHOLOGY OF CHRONIC MANGANESE EXPOSURE

描述(申请人提供)：帕金森病(PD)是一种常见的神经退行性疾病，在北美有100多万人受到影响。在大多数情况下，帕金森病的原因尚不清楚，但环境中的金属暴露可能是一个危险因素。这笔赠款的主要目标是比较南非锰(Mn)矿工和南非黄金(Au)矿工的大脑，以调查长期暴露于锰的工人将出现典型的早期帕金森氏症的神经病理结果的假设，以进一步阐明环境金属暴露在帕金森氏病发病机制中的作用。为了实现这一目标，我们将对南非锰矿矿工的大脑和南非金矿矿工的参照脑进行神经病理学检查。神经元、星形胶质细胞和小胶质细胞将在下列固定的脑区进行体视学计数：苍白球内侧区、黑质致密部、蓝斑和嗅球。我们还将尝试将立体细胞计数与每个感兴趣区域的组织锰沉积相关联。在对组织进行α-突触核蛋白抗体染色后，还将评估路易小体、路易氏突起和α-突触核蛋白聚集体的分布。此外，暴露于锰的矿工的神经元数量和胶质增生程度或其他损伤标志将与重建的职业性锰暴露相关，以及通过就业健康档案获得的过去神经学检查的帕金森症临床迹象。α-突触核蛋白及其聚集体的数量将通过Western印迹在这些相同的大脑区域进行量化。此外，矿工纹状体中的残留酪氨酸羟化酶(TH)将被检测。我们将尝试将锰矿工的α-突触核蛋白聚集和残留纹状体TH与重建的职业性锰暴露以及现有就业健康档案中帕金森症的临床迹象相关联。该项目涉及美国PD和MN研究人员与南非国家职业健康研究所在世界领先的MN生产国进行的独特的国际合作。公共卫生相关性：这项研究的结果将更好地了解金属暴露，特别是锰与帕金森病之间的关系。这项研究的发现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.