Ferritin Induced Neurodegeneration

描述（由申请人提供）：铁在一些神经退行性疾病（如阿尔茨海默病和帕金森病）中发生变性的脑区域积累。然而，铁在神经退行性过程中的确切作用尚不清楚。该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。我们最近描述了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。心衰是一种运动障碍，其神经病理学特征是整个中枢神经系统中铁蛋白包络体（IBs）和铁的异常积累（Vidal 2011）。由于心衰患者的铁代谢异常与神经退行性变直接相关，因此对该疾病的研究具有远超单基因疾病的深远意义。在之前的资助期内，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。基于我们之前的工作，我们提出了涉及HF发展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。一个关键问题是这些机制是单独作用还是共同作用导致心衰的神经退行性变。由突变体FTL亚基组成的铁蛋白显示出铁蛋白4倍孔的破坏和c端肽的解开和延伸。我们假设这些结构问题导致铁蛋白功能失调，产生游离羟基自由基，铁催化铁蛋白氧化和IB形成。此外，由于铁蛋白功能障碍导致

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.