All cells in organisms ranging from yeast to humans utilize iron as a cofactor or structural element of proteins that function in diverse and critical cellular functions. However, deregulation of the homeostatic mechanisms regulating iron metabolism resulting in a reduction or excess of iron within the cell or outside of it can have serious effects to the health of cells and the organism. This review provides a brief overview of the molecular and cellular mechanisms regulating iron physiology, including the molecules and processes regulating iron uptake, its storage and utilization, its recycling, and its release from the cell, such that the cellular iron levels are sufficient to meet metabolic demand but below those that cause permanent damage. The major focus of review is on the pathological consequences of dysregulation of these homeostatic mechanisms, focusing on the brain. Current advances on the role of iron accumulation to the pathogenesis of rare neurological disorders caused by genetic mutations as well as to the more prevalent and age-associated neurodegenerative diseases are described.

Impact statement

Brain degenerative disorders, which include some neurodevelopmental disorders and age-associated diseases, cause debilitating neurological deficits and are generally fatal. A large body of emerging evidence indicates that iron accumulation in neurons within specific regions of the brain plays an important role in the pathogenesis of many of these disorders. Iron homeostasis is a highly complex and incompletely understood process involving a large number of regulatory molecules. Our review provides a description of what is known about how iron is obtained by the body and brain and how defects in the homeostatic processes could contribute to the development of brain diseases, focusing on Alzheimer’s disease and Parkinson’s disease as well as four other disorders belonging to a class of inherited conditions referred to as neurodegeneration based on iron accumulation (NBIA) disorders. A description of potential therapeutic approaches being tested for each of these different disorders is provided.

中文翻译：

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铁过量：铁含量升高和退行性脑部疾病。

从酵母到人类，生物体中的所有细胞都利用铁作为蛋白质的辅助因子或结构元素，这些蛋白质在多种关键的细胞功能中发挥作用。然而，调节铁代谢的稳态机制失调导致细胞内或细胞外铁减少或过量，可能对细胞和生物体的健康产生严重影响。本综述简要概述了调节铁生理学的分子和细胞机制，包括调节铁的吸收、储存和利用、回收以及从细胞中释放的分子和过程，以使细胞铁水平足以满足代谢需求但低于造成永久性损伤的代谢需求。综述的主要焦点是这些稳态机制失调的病理后果，重点关注大脑。描述了铁积累对基因突变引起的罕见神经系统疾病以及更普遍和与年龄相关的神经退行性疾病的发病机制的作用的最新进展。

 影响报告

脑退行性疾病，包括一些神经发育障碍和与年龄相关的疾病，会导致神经功能缺陷，通常是致命的。大量新证据表明，大脑特定区域神经元中铁的积累在许多此类疾病的发病机制中发挥着重要作用。铁稳态是一个高度复杂且不完全了解的过程，涉及大量调节分子。我们的综述描述了身体和大脑如何获取铁以及体内平衡过程的缺陷如何导致脑部疾病的发展，重点关注阿尔茨海默病和帕金森病以及其他四种属于脑部疾病的疾病。一类遗传性疾病，称为基于铁积累的神经变性 (NBIA) 疾病。提供了针对每种不同疾病正在测试的潜在治疗方法的描述。