Contributions of Iron Regulatory Proteins and Ferroptosis to Neurodegeneration

1个项目摘要 2氧化还原活性铁水平在正常衰老和神经退行性疾病进展过程中积累。因此， 3种减轻铁介导的细胞损伤的策略可以用来促进健康衰老和预防 4神经退行性下降。一种这样的方法可能是通过预防铁性下垂，这是铁介导的一种形式 5程序性细胞死亡。然而，我们必须首先了解细胞是如何操纵铁的体内平衡调节剂的。 6在我们能够完全开发出针对铁的治疗策略之前，新陈代谢对疾病有贡献。铁的监管 7蛋白1和2(irp1和irp2)是细胞内铁稳态的主要调节者，因为它们协调 8铁储存、吸收和外排相关蛋白的表达。然而，IRPS在细胞内的作用和调节 9铁性下垂尚不清楚。蒙哥马利实验室的长期目标是了解收购如何夸大 10量的铁促进新陈代谢紊乱，从而导致铁介导的疾病进展。首要目标是 11这项工作的目的是确定IRP mRNA结合活性如何影响细胞对铁链细胞死亡的敏感性。这个 12中心假设是IRP mRNA结合活性的增加促进了细胞铁的积累，并促进了 13铁性细胞死亡。为了验证这一假设，在目标1中，我们将使用从注射的斑马鱼中分离出的初级神经元 14用IRP1和IRP2吗啡来评估IRP依赖的铁链细胞死亡易感性的差异。 15有趣的是，经过病理修饰的tau也可以抑制铁的外流，从而导致铁的积累 16与神经元性下垂和痴呆进展有关，但IRPS在铁性下垂和tau介导的作用中的作用 17神经退行性变仍未明确。因此，在目标2中，我们将利用斑马鱼模型来确定变态反应的程度 18，铁下垂抑制以IRP依赖的方式保护神经退行性变。这类研究是 19很重要，因为铁性下垂的不受控制的激活可以进一步加剧tau介导的神经变性 20种病理疾病，如阿尔茨海默病和相关痴呆(ADRD)。因此，这项工作的发现可能会导致 21改进了治疗策略，以减轻铁相关的ADRD风险并改善ADRD患者的预后。

1 Project Summary 2 Levels of redox active iron accumulate during both normal aging and neurodegenerative disease progression. Thus, 3 strategies for mitigating iron-mediated cellular damage could be used to promote healthy aging and protect against 4 neurodegenerative decline. One such approach may be through the prevention of ferroptosis, a form of iron-mediated 5 programmed cell death. However, we must first understand how cells manipulate the homeostatic regulators of iron 6 metabolism to contribute to disease before we can fully develop iron-targeted therapeutic strategies. The iron regulatory 7 proteins 1 and 2 (IRP1 and IRP2) are the master regulators of intracellular iron homeostasis because they coordinate the 8 expression of proteins involved in iron storage, uptake, and efflux. Yet, the roles and regulation of IRPs during cellular 9 ferroptosis remain unknown. The long-term goal of the Montgomery lab is to understand how acquisition of exaggerated 10 amounts of iron promote metabolic perturbations that lead to iron-mediated disease progression. The primary objective 11 of this work is to establish how IRP mRNA binding activity influences cellular sensitivity to ferroptotic cell death. The 12 central hypothesis is that increased IRP mRNA binding activity promotes cellular iron accumulation and facilitates 13 ferroptotic cell death. To test this hypothesis, in Aim 1, we will utilize primary neurons isolated from zebrafish injected 14 with IRP1 and IRP2 morpholinos to assess IRP-dependent differences in susceptibility to ferroptotic cell death. 15 Intriguingly, pathologically modified tau can also inhibit iron efflux, and the resulting iron accumulation has been 16 associated with neuronal ferroptosis and dementia progression, but the role of IRPs in ferroptosis and tau-mediated 17 neurodegeneration remains undefined. Thus, in Aim 2, we will utilize a zebrafish model of tauopathy determine the extent 18 to which ferroptosis inhibition protects against neurodegeneration in and IRP-dependent manner. Such studies are 19 important because uncontrolled activation of ferroptosis can further exacerbate neurodegeneration in tau-mediated 20 pathologies such as Alzheimer’s disease and related dementias (ADRD). Thus, findings from this work could lead to 21 improved therapeutic strategies for mitigating iron associated ADRD risks and improving ADRD patient outcomes.