Iron Acquisition Mechanisms in Oligodendrocytes

根据世界卫生组织的说法，缺铁是世界上最重要的营养障碍。铁对正常的神经功能至关重要，缺铁会导致认知和运动障碍，这些障碍可能持续一生，而且往往是不可逆的。许多与缺铁相关的神经系统问题可以追溯到髓鞘形成不足。铁在髓鞘形成中的作用是在过去20年中建立的，PI实验室的数据显示，少突胶质细胞比大脑中任何其他类型的细胞对铁的染色更显著。这些数据与髓鞘形成中所涉及的铁需要酶的相对高浓度相一致。然而，一个重要的遗漏，在范例中关于铁和少突胶质细胞的功能，少突胶质细胞如何获得铁，尚未确定。我们和其他人报道，尽管白色物质束中的铁水平相对较高，但在白色物质中没有可检测到的转移受体（铁获取的传统细胞机制）。甚至当铁缺乏严重到导致髓鞘形成不足时，在白色物质中也检测不到转移受体的表达。我们提出的总体假设是，H-铁蛋白是少突胶质细胞，而不是转铁蛋白的铁输送车辆。最近，脑信号蛋白家族的一员，T细胞免疫球蛋白粘蛋白结构域2（Tim-2）被发现结合H-铁蛋白。因此，这一系列研究的概念框架是Tim-2是由少突胶质细胞选择性表达的铁蛋白结合蛋白，并且是这些细胞获得产生和维持髓鞘所需的铁的机制。这项研究的意义在于，我们发现了一种新的、发育调节的、选择性表达的少突胶质细胞铁获得受体。由于Tim-2的唯一其他已知配体是Sema 4A，一种在抗原呈递细胞和活化的带T淋巴细胞上表达的蛋白质，因此在本文提出的研究之后可以追求的潜在重要的未来方向将是探索免疫系统和少突胶质细胞之间通过Tim-2在少突胶质细胞上表达的可能性，其可以影响脱髓鞘疾病。该项目具有创新性，因为其目的是建立以下关于铁在eNS髓鞘形成中的作用的新数据：i）H-铁蛋白是少突胶质细胞获得铁的决定性机制; ii）少突胶质细胞上的H-铁蛋白结合蛋白是Tim-2，iii）H-铁蛋白可用作递送载体，以改善缺铁后的髓鞘形成。铁是如何管理和交付给少突胶质细胞的知识，以及铁获取蛋白的表达时机，可以预期为治疗由铁缺乏和脱髓鞘疾病引起的发育性髓鞘形成不足以及成人如多发性硬化症的髓鞘再生尝试提供干预策略。

According to The World Health Organization, iron deficiency is the foremost nutritional disorder in the world. Iron is essential for normal neurological function and iron deficiency results in cognitive and motor impairments that can last throughout life, and are often irreversible. Many of the neurological problems associated with iron deficiency can be traced to hypomyelination. The role of iron in myelination was established over the past 20 years, by data from the PI's laboratory revealing that oligodendrocytes stain more prominently than any other cell type in the brain for iron. These data were consistent with the relatively high concentration of iron-requiring enzymes involved in myelination. However, a significant omission in the paradigm regarding iron and oligodendrocyte function, how oligodendrocytes acquire iron, has not been identified. We and others reported that despite the relatively high levels of iron in white matter tracts, there was no detectable transferring receptor (the traditional cellular mechanism for iron acquisition) in white matter. Even when iron deficiency is so severe as to cause hypomyelination, transferring receptor expression in white matter is not detectable. We propose the overall hypothesis that H-ferritin is the iron delivery vehicle for oligodendrocytes instead of transferrin. Recently, a member of the semaphorin family, T-cell immunoglobulin mucin domain 2 (Tim-2) was discovered to bind H-ferritin. Thus, the conceptual framework for this line of research is that Tim-2 is the ferritin binding protein that is selectively expressed by oligodendrocytes and is the mechanism by which these cells obtain the iron that is required to produce and sustain myelin. The significance of the proposed research is that we have found a novel, developmentally regulated, selectively expressed, receptor for iron acquisition on oligodendrocytes. Because the only other known ligand for Tim-2 is Sema4A, a protein expressed on antigen presenting cells and activated Band T lymphocytes, a potentially significant future direction that can be pursued following the studies proposed herein will be to explore the possibility of a connection between the immune system and oligodendrocytes via Tim-2 expression on oligodendrocytes that could affect demyelinating disorders. The project is innovative because the aims are designed to establish the following new data on the role of iron in myelination of eNS: i) H-ferritin is the definitive mechanism by which oligodendrocytes acquire iron; ii) the H-ferritin binding protein on oligodendrocytes is Tim-2, iii) that H-ferritin protein can be used as a delivery vehicle to improve myelination following iron deficiency. The knowledge of how iron is managed and delivered to oligodendrocytes as well as the timing of expression of iron acquisition proteins can be expected to inform intervention strategies for the treatment of developmental hypomyelination resulting from iron deficiency and demyelinating disorders and remyelination attempts in the adult such as Multiple Sclerosis.