Department of Veterinary Sciences, University of Wyoming, Laramie, WY, United States of America.
Neuroscience Graduate Program, University of Wyoming, Laramie, WY, United States of America.
PLoS One. 2021 May 14;16(5):e0250606. doi: 10.1371/journal.pone.0250606. eCollection 2021.
Huntington's disease (HD) is a neurodegenerative disorder caused by a dominant CAG-repeat expansion in the huntingtin gene. Microglial activation is a key feature of HD pathology, and is present before clinical disease onset. The kynurenine pathway (KP) of tryptophan degradation is activated in HD, and is thought to contribute to disease progression. Indoleamine-2,3-dioxygenase (IDO) catalyzes the first step in this pathway; this and other pathway enzymes reside with microglia. While HD brain microglia accumulate iron, the role of iron in promoting microglial activation and KP activity is unclear. Here we utilized the neonatal iron supplementation model to investigate the relationship between iron, microglial activation and neurodegeneration in adult HD mice. We show in the N171-82Q mouse model of HD microglial morphologic changes consistent with immune activation. Neonatal iron supplementation in these mice promoted neurodegeneration and resulted in additional microglial activation in adults as determined by increased soma volume and decreased process length. We further demonstrate that iron activates IDO, both in brain lysates and purified recombinant protein (EC50 = 1.24 nM). Brain IDO activity is increased by HD. Neonatal iron supplementation further promoted IDO activity in cerebral cortex, altered KP metabolite profiles, and promoted HD neurodegeneration as measured by brain weights and striatal volumes. Our results demonstrate that dietary iron is an important activator of microglia and the KP pathway in this HD model, and that this occurs in part through a direct effect on IDO. The findings are relevant to understanding how iron promotes neurodegeneration in HD.
亨廷顿病（HD）是一种神经退行性疾病，由亨廷顿基因中的 CAG 重复扩展引起。小胶质细胞激活是 HD 病理学的一个关键特征，并且在临床疾病发作之前就存在。色氨酸降解的犬尿氨酸途径（KP）在 HD 中被激活，并且被认为有助于疾病进展。吲哚胺 2,3-双加氧酶（IDO）催化该途径的第一步；这种酶和其他途径的酶都存在于小胶质细胞中。虽然 HD 大脑中的小胶质细胞积累了铁，但铁在促进小胶质细胞激活和 KP 活性中的作用尚不清楚。在这里，我们利用新生期铁补充模型来研究铁、小胶质细胞激活和成年 HD 小鼠中的神经退行性变之间的关系。我们在 N171-82Q HD 小鼠模型中显示小胶质细胞形态发生变化，与免疫激活一致。在这些小鼠中，新生期铁补充促进了神经退行性变，并导致成年后小胶质细胞的额外激活，表现为细胞体体积增加和突起长度减少。我们进一步证明，铁在脑匀浆和纯化的重组蛋白中均能激活 IDO（EC50=1.24 nM）。HD 中脑 IDO 活性增加。新生期铁补充进一步促进了大脑皮层 IDO 活性、改变了 KP 代谢产物谱，并通过大脑重量和纹状体体积来促进 HD 神经退行性变。我们的结果表明，膳食铁是这种 HD 模型中小胶质细胞和 KP 途径的重要激活剂，而这种作用部分是通过对 IDO 的直接作用实现的。这些发现与理解铁如何促进 HD 中的神经退行性变有关。
