HFE gene variants, iron, and lipids: a novel connection in Alzheimer's disease.
HFE gene variants, iron, and lipids: a novel connection in Alzheimer's disease.
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HFE基因变体，铁和脂质：阿尔茨海默氏病的新型联系。
DOI：
10.3389/fphar.2014.00165
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发表时间：
2014
影响因子：
5.6
通讯作者：
Connor JR
中科院分区：
文献类型：
--
作者：
Ali-Rahmani F;Schengrund CL;Connor JR
在几种神经退行性疾病中，大脑中的铁积累和相关的氧化应激一直被发现。已经进行了多项基因研究，试图确定神经退行性疾病的原因，但直接联系一直很少。在铁的领域，HFE基因的变异产生了一种参与细胞铁调节的蛋白质，与包括大脑在内的多个器官中的铁积累有关。也有大量的流行病学、遗传学和分子证据表明，在几种神经退行性疾病中，特别是阿尔茨海默病(AD)，胆固醇稳态被破坏。尽管已经努力确定可能引发与神经退行性疾病相关的病理事件的因素，但这些因素大多仍不清楚。由于与AD相关的分子表型，如氧化应激、突触失败、神经元丢失和认知能力下降，已被证明是许多途径中断的结果，人们很容易争辩说，所看到的表型可能不是由线性事件序列产生的。因此，需要一种多靶点的方法来理解像AD这样的复杂障碍。只有当了解不同途径之间的相互作用以及环境因素对它们的潜在影响时，才能实现这一点。为此，这篇综述讨论了铁和胆固醇在神经退行性疾病中的作用和相互作用。它强调了HFE(H63D-和C282Y-HFE)基因变异对铁和胆固醇代谢的影响，以及它们如何有助于理解复杂神经退行性疾病的病因。
Iron accumulation and associated oxidative stress in the brain have been consistently found in several neurodegenerative diseases. Multiple genetic studies have been undertaken to try to identify a cause of neurodegenerative diseases but direct connections have been rare. In the iron field, variants in the HFE gene that give rise to a protein involved in cellular iron regulation, are associated with iron accumulation in multiple organs including the brain. There is also substantial epidemiological, genetic, and molecular evidence of disruption of cholesterol homeostasis in several neurodegenerative diseases, in particular Alzheimer’s disease (AD). Despite the efforts that have been made to identify factors that can trigger the pathological events associated with neurodegenerative diseases they remain mostly unknown. Because molecular phenotypes such as oxidative stress, synaptic failure, neuronal loss, and cognitive decline, characteristics associated with AD, have been shown to result from disruption of a number of pathways, one can easily argue that the phenotype seen may not arise from a linear sequence of events. Therefore, a multi-targeted approach is needed to understand a complex disorder like AD. This can be achieved only when knowledge about interactions between the different pathways and the potential influence of environmental factors on them becomes available. Toward this end, this review discusses what is known about the roles and interactions of iron and cholesterol in neurodegenerative diseases. It highlights the effects of gene variants of HFE (H63D- and C282Y-HFE) on iron and cholesterol metabolism and how they may contribute to understanding the etiology of complex neurodegenerative diseases.
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