Effects of HFE H63D on Brain Mn Accumulation and Neurotoxicity

项目概要/摘要 锰（Mn）是许多细胞过程的必需辅因子，但在升高的浓度下， 对大脑有神经毒性作用迄今为止，对锰暴露儿童和 电焊工一直表明，慢性锰暴露（X）与运动缺陷有关， 神经行为结果（Y）。此外，磁共振成像（MRI）显示，Mn 暴露和结果与脑Mn累积（M）相关。虽然这些协会提出了 尽管人们对基于成像的安全指南的发展感兴趣，但目前尚不清楚大脑Mn 蓄积可能介导锰暴露与运动和神经行为结果之间的关系 （X→M→Y）。这种缺乏理解导致一些人试图进行复杂的高维数据分析， 解卷积锰暴露个体神经毒性的潜在关系。然而，迄今为止， 解释了可能具有显著调节作用的常见遗传变异。重要的是， 已知Mn水平受铁（Fe）水平和Fe调节蛋白表达的影响。化学 类似地，Mn和Fe通过共享运输机制在细胞内和细胞外隔室之间移动。 人血色病蛋白（HFE）是一种铁调节蛋白， 促进Mn进入大脑。在位置63处的HFE组氨酸至天冬氨酸取代（H63 D）是一个HFE突变。 通常携带导致HFE部分功能丧失的基因变体。因此，这个问题的核心假设 奖学金的应用是，HFE H63 D缓和焊接，脑锰积累， 以及神经行为和运动结果。在这样做的过程中，H63 D可能会缓和长期的神经毒性作用。 锰暴露。揭示这些影响尤其重要

PROJECT SUMMARY/ABSTRACT Manganese (Mn) is an essential cofactor for many cellular processes, but at elevated concentrations is known to exert neurotoxic effects on the brain. To date, population-based studies of Mn-exposed children and welders have consistently shown that chronic Mn exposure (X) is associated with deficits in motor and neurobehavioral outcomes (Y). Additionally, magnetic resonance imaging (MRI) has shown that both Mn exposure and outcomes are associated with brain Mn accumulation (M). While these associations have raised interest in the development of imaging-based safety guidelines, it is presently unknown as to how brain Mn accumulation may mediate the relationship between Mn exposure and motor and neurobehavior outcomes (X→M→Y). This lack of understanding has led some to attempt complex, high-dimensional data analyses to deconvolve the underlying relationships governing neurotoxicity in Mn-exposed individuals. However, few so far have accounted for common genetic variants that are likely to have significant moderating effects. Importantly, Mn levels are known to be influenced by iron (Fe) levels and the expression of Fe-regulatory proteins. Chemically similar, Mn and Fe move between intra- and extracellular compartments through shared transport mechanisms. The human hemochromatosis protein (HFE) is an Fe-regulatory protein that negatively regulates mechanisms facilitating Mn entry into the brain. The HFE histidine-to-aspartate substitution at position 63 (H63D) is a commonly carried gene variant that results in HFE partial loss-of-function. Thus, the central hypothesis of this fellowship application is that HFE H63D moderates the relationships between welding, brain Mn accumulation, and neurobehavioral and motor outcomes. In doing so, H63D may moderate the neurotoxic effects of prolonged Mn exposure. Uncovering these effects is of particular