Gene-environment interactions between manganese exposure and Huntington disease

描述（由申请人提供） 这项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。本提案中包含的工作重点是锰（Mn）暴露对亨廷顿病（HD）病理生理学的影响。锰过量暴露与铁稳态和能量代谢的变化有关，并已被证明可促进固有淀粉样蛋白的聚集。此外，大脑中Mn积累的主要部位是纹状体，其中含有HD中最脆弱的神经元。由突变HD基因引起的慢性神经毒性应激与铁稳态的改变、细胞能量代谢的缺陷以及疾病蛋白质积累成淀粉样包涵体有关。HD和Mn神经毒性的病理生理学的这些相似性表明Mn暴露可能调节HD神经病理学。利用范德比尔特大学国家环境健康科学研究所（NIEHS）分子毒理学核心中心提供的试点项目资源，研究人员测试了锰暴露增加对HD纹状体细胞模型的影响。这些初步实验揭示了一个令人惊讶和令人兴奋的结果，即突变HD纹状体细胞对Mn毒性具有抗性，并且在病理生理学上相关的Mn暴露抑制突变HD表型。该提案将利用细胞和小鼠疾病模型来研究这种基因-环境神经保护相互作用的分子基础，并评估Mn暴露调节HD发病机制的潜力。这些研究围绕三个具体目标进行。在第一个这些研究人员将定义特定的HD蛋白质结构域和特定的细胞介质的锰行动的Mn-HD基因-环境相互作用的功能域映射和评估具有类似的神经毒性特性的其他金属的贡献。在第二个目标中，研究人员将利用HD的细胞和动物模型，通过生物化学和生物物理蛋白质测定来确定锰离子是否改变HD蛋白的构象或功能特性。然后，在第三个目标中，研究者将评价Mn毒性和HD神经病理学的已知病理学终点，以阐明体内Mn-HD相互作用的生理过程。这些具体目标与NIEHS的使命一致，因为它们检查特定环境毒物对人类疾病病理生理过程的影响。最后，通过探索一个基因-环境界面，缓和的发病和进展的HD，本研究旨在揭示机制的细节，如何收敛的遗传和环境因素可以增强或抑制疾病。

DESCRIPTION (provided by applicant) 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, the investigators 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 the investigators 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 the investigators 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 the investigators 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.