Ferritin Induced Neurodegeneration

描述（由申请人提供）：铁在几种神经退行性疾病（如阿尔茨海默病和帕金森病）中经历变性的脑区域中积累。然而，铁在神经退行性过程中的确切作用尚不清楚。本项目的长期目标是确定和表征异常铁代谢可能参与神经变性的机制。我们最近的特点是神经退行性疾病遗传性铁蛋白病（HF），这是由铁蛋白轻多肽（FTL）基因突变引起的。HF是一种运动障碍，其神经病理学特征为铁蛋白包涵体（IB）和铁在整个CNS中异常蓄积（Vidal 2011）。由于HF中的异常铁代谢与神经变性直接相关，因此对这种疾病的研究具有超越这种单基因疾病的深远意义。在上一个资助期间，我们表征了HF中IB的生化组成，确定了导致铁过载和IB形成的结构缺陷，并开发和表征了唯一可用的HF动物模型。基于我们以前的工作，我们提出HF发展中涉及的两个关键毒性病理机制是i）铁蛋白正常功能的丧失和ii）铁蛋白毒性功能的获得。一个关键的问题是这些机制是独立作用还是共同作用导致HF的神经退行性变。由突变FTL亚基组成的铁蛋白显示铁蛋白4倍孔的破坏以及C-末端肽的解开和延伸。我们推测，这些结构问题导致铁蛋白功能障碍，产生自由羟基自由基，铁催化氧化的铁蛋白，和IB的形成。此外，由于铁蛋白功能障碍导致 铁代谢紊乱，我们提出，在中枢神经系统中的铁水平的调节可以延缓（也许停止）疾病的进展。为了检验我们的假设，我们的具体目标是：具体目标1：确定铁桥接是导致HF中IB形成的常见机制，铁蛋白4倍孔的破坏是导致铁蛋白功能障碍和铁蛋白氧化修饰的常见事件。具体目标二：使用基于HF相关p.Phe167SerfsX26多肽的表达和铁蛋白Ft 1多肽合成的遗传减少的细胞模型来表征铁蛋白功能丧失和铁蛋白毒性功能获得。具体目标3：在体内表征CNS中铁蛋白的铁储存功能丧失的后果，并研究铁在HF病理生理学中的作用。 公共卫生相关性：该项目将研究铁在神经退行性疾病遗传性铁蛋白病中的作用，其中异常的铁代谢与神经退行性疾病直接相关。我们将进行一系列的体外实验，以确定HF的分子基础，并使用动物模型进行体内研究，以获得更多的知识，疾病的基础上，并测试某种形式的治疗。我们的工作将为铁代谢异常在神经退行性变中的作用提供新的见解。

DESCRIPTION (provided by applicant): Iron accumulates in brain regions that undergo degeneration in several neurodegenerative diseases such as Alzheimer disease and Parkinson disease. However, the precise role of iron in the neurodegenerative process is unclear. The long term goals of this project are to identify and characterize the mechanism(s) by which abnormal iron metabolism may be involved in neurodegeneration. We recently characterized the neurodegenerative disease hereditary ferritinopathy (HF), which is caused by mutations in the ferritin light polypeptide (FTL) gene. HF is a movement disorder that is neuropathologically characterized by abnormal accumulation of ferritin inclusion bodies (IBs) and iron throughout the CNS (Vidal 2011). Since abnormal iron metabolism in HF is directly linked to neurodegeneration, the study of this disease has far- reaching implications beyond this single gene disorder. During the previous funding period, we characterized the biochemical composition of IBs in HF, identified the structural defect that leads to iron overload and IB formation, and developed and characterized the only available animal model for HF. Based on our previous work, we proposed that the two key toxic pathologic mechanisms implicated in the development of HF are i) a loss of the normal function of ferritin and ii) a gain of a toxic functin of ferritin. A key question is whether these mechanisms are acting independently or together to lead to neurodegeneration in HF. Ferritin composed by mutant FTL subunits show disruption of ferritin 4-fold pores and unraveling and extension of the C-terminal peptide. We hypothesize that these structural problems cause ferritin malfunction, generation of free hydroxyl radicals, iron-catalyzed oxidation of ferritin, and IB formation. In addition, since ferritin malfunction leads to deranged iron metabolism, we propose that modulation of iron levels in the CNS could delay (and perhaps stop) the progression of the disease. In order to test our hypotheses, our specific aims are: Specific Aim 1: to establish that iron bridging is the common mechanism leading to IB formation in HF and that the disruption of ferritin 4-fold pores is the common event that leads to ferritin malfunction and oxidative modification of ferritin. Specific Aim 2: to characterize ferritn loss-of function and ferritin gain of toxic function using cellular models based on the expression of the HF-associated p.Phe167SerfsX26 polypeptide and the genetic reduction of ferritin Ftl polypeptide synthesis. Specific Aim 3: To characterize in vivo the consequences of the loss of the iron storage function of ferritin in the CNS and investigate the role of iron in the pathophysiology of HF. PUBLIC HEALTH RELEVANCE: This project will investigate the role of iron in the neurodegenerative disease hereditary ferritinopathy, in which abnormal iron metabolism is directly linked to neurodegeneration. We will perform a series of in vitro experiments to determine the molecular basis of HF and use animal models to perform in vivo studies to gain additional knowledge on the basis of the disease and to test some form of therapy. Our work will provide new insights into the role of abnormal iron metabolism in neurodegeneration.