Gene-environment interactions between manganese exposure and Huntington disease

项目总结/摘要 拟议工作的长期目标是了解环境和遗传因素如何相互作用 影响选择性神经病理学本提案所载的工作侧重于以下方面的影响： 锰（Mn）暴露对亨廷顿病（HD）病理生理学的影响。锰的过度暴露 与铁稳态和能量代谢的变化有关，并已被证明可以促进 固有淀粉样蛋白的聚集。此外，脑中Mn积累的主要部位是 纹状体，其中包含HD中最脆弱的神经元。慢性神经毒性应激 突变的HD基因所呈现的铁缺乏与铁稳态的改变、细胞内铁的缺乏和细胞内铁的缺乏有关。 能量代谢和疾病蛋白质积累成淀粉样内含物。这些相似之处， HD和锰神经毒性病理生理学提示锰暴露可能调节HD 神经病理学利用国家环境卫生研究所提供的试点项目资源 我们在范德比尔特大学的NIEHS分子毒理学核心中心测试了 HD纹状体细胞模型中Mn暴露增加。这些试点实验揭示了一个令人惊讶的， 令人兴奋的结果是，突变的HD纹状体细胞对Mn毒性具有抗性，并且与病理生理学相关 暴露于Mn抑制突变HD表型。该提案将利用细胞和小鼠模型， 研究这种基因-环境神经保护相互作用的分子基础， 锰暴露调节HD发病机制的潜力。这些研究围绕三个具体的 目标。在第一部分中，我们将定义特定HD蛋白结构域和特定细胞因子的贡献。 通过功能结构域作图， 评估具有类似神经毒性特性的其他金属。在第二个目标中，我们将确定Mn离子是否改变 通过生物化学和生物物理蛋白质分析确定HD蛋白的构象或功能特性 利用HD的细胞和动物模型。然后，在第三个目标中，我们将评估已知的病理终点 锰毒性和HD神经病理学，以阐明Mn-HD的生理过程 体内相互作用。这些具体目标与NIEHS的使命是一致的，因为它们检查了 特定环境毒物对人类疾病病理生理过程的影响。最后通过 本研究旨在探索一种基因-环境界面，以调节HD的发病和进展， 揭示了趋同的遗传和环境因素如何增强或抑制 疾病项目叙述 随着人口老龄化，神经退行性疾病对个人、社会和经济的影响迅速增加。 不断升级无论是环境毒物，如锰，还是遗传损伤，如亨廷顿病， 基因和环境因素如何相互作用来调节疾病， 明白该提案将研究锰暴露与 亨廷顿氏病，有可能缓和人类疾病，优先考虑治疗目标， 提供了对选择性神经元变性基础的深入了解。

PROJECT SUMMARY/ABSTRACT The long-term objective of the proposed work is to understand how environmental and genetic factors interact to influence selective neuropathology. The work contained within this proposal focuses on the influence of manganese (Mn) exposure on the pathophysiology of Huntington's disease (HD). Mn over-exposure has been associated with changes in iron homeostasis and energy metabolism, and has been shown to promote the aggregation of intrinsically amyloidogenic proteins. Furthermore, a major site of Mn accumulation in the brain is the corpus striatum, which contains the neurons most vulnerable in HD. The chronic neurotoxic stress rendered by the mutant HD gene has been associated with alterations in iron homeostasis, deficits in cellular energy metabolism, and accumulation of the disease protein into amyloid-like inclusions. These similarities in the pathophysiology of HD and Mn neurotoxicity suggest a potential for Mn exposure to modulate HD neuropathology. Using pilot project resources provided by the National Institute of Environmental Health Sciences (NIEHS) Core Center in Molecular Toxicology at Vanderbilt University we tested the influence of increased Mn exposure on a striatal cell model of HD. These pilot experiments revealed a surprising and exciting result, that mutant HD striatal cells are resistant to Mn toxicity and pathophysiologically relevant exposures to Mn suppress mutant HD phenotypes. This proposal will utilize cellular and mouse models of disease to examine the molecular basis of this gene-environment neuroprotective interaction and evaluate the potential of Mn exposure to modulate HD pathogenesis. These studies are organized around three Specific aims. In the first of these we will define the contribution of specific HD protein domains and specific cellular mediators of Mn action to the Mn-HD gene-environment interaction by functional domain mapping and evaluating other metals with similar neurotoxic properties. In the second aim we will determine if Mn ions alter the conformational or functional properties of the HD protein by biochemical and biophysical protein assays utilizing cellular and animal models of HD. Then, in the third aim we will evaluate known pathological endpoints of Mn toxicity and HD neuropathology to elucidate the physiological processes that underlie the Mn-HD interaction in vivo. These specific aims are aligned with the mission of the NIEHS in that they examine the impact of a specific environmental toxicant on the pathophysiological processes of human disease. Finally, by exploring a gene-environment interface that moderates the onset and progression of HD, this study seeks to reveal mechanistic detail for how convergent genetic and environmental factors can enhance or suppress disease. PROJECT NARRATIVE With an aging population the personal, social and economic impact of neurodegenerative disease is rapidly escalating. Both environmental toxicants, such as manganese, and genetic insults, as in Huntington's disease, contribute to disease, but how genetic and environmental factors intersect to modulate disease is poorly understood. This proposal will examine an interaction discovered between manganese exposure and Huntington's disease that has the potential to moderate human disease, prioritize therapeutic targets, and provide insight into the basis of selective neuronal degeneration.