Ferritin Induced Neurodegeneration

描述(申请人提供)：几种神经退行性疾病被认为是蛋白质构象异常的障碍。它们中的许多是由于突变导致蛋白质构象稳定性降低，从而阻止多肽的正常折叠或与其他亚基或稳定辅因子的结合。我们描述了一种神经退行性疾病，其特征是核内铁蛋白包涵体的存在与铁蛋白轻链(FTL)基因的新突变相关。我们假设突变导致FTL多肽的主要构象变化，导致铁蛋白包涵体的异常积聚和神经变性。我们的长期目标是确定在铁蛋白包涵体的形成和神经退变过程中所涉及的结构基础和机制。这项工作除了这种单基因紊乱外，还具有深远的影响，因为许多其他神经退行性疾病也以核内包涵体的存在为特征。此外，这些研究将增加我们对细胞铁代谢中断在更常见的神经退行性疾病中的后果的理解。在具体目标1中，我们将确定突变对FTL亚基稳定性以及铁蛋白组装和功能的影响。详细的生化分析将为了解突变在疾病中的作用提供基础。在特定的目标2中，我们将确定转基因小鼠脑组织中铁蛋白沉积的时间和空间模式，并确定受影响神经元中铁代谢的失调是否与神经退行性变有关。这些研究将提供对基本病理机制的见解。在具体目标3中，我们将确定突变铁蛋白是否获得了对神经元有害的毒性功能。我们将研究铁蛋白和核蛋白的相互作用，以及泛素-蛋白酶体途径在铁蛋白异常积聚和疾病发病机制中的作用。

DESCRIPTION (provided by applicant): Several neurodegenerative diseases are recognized as disorders of abnormal protein conformation. Many of them arise from mutations that result in a protein with decreased conformational stability that prevents the normal folding or the association of the polypeptide with other subunits or stabilizing cofactors. We described a neurodegenerative disease characterized by the presence of intranuclear ferritin inclusion bodies associated with a novel mutation in the ferritin light chain (FTL) gene. We hypothesize that the mutation causes a major conformational change in the FTL polypeptide, leading to the abnormal accumulation of ferritin inclusion bodies and neurodegeneration. Our long-term objective is to define the structural basis and mechanisms that are implicated in the formation of ferritin inclusion bodies and in the neurodegenerative process. This work has far-reaching implications beyond this single gene disorder, since many other neurodegenerative diseases are also characterized by the presence of intranuclear inclusion bodies. Furthermore, these studies will increase our understanding of the consequences of the disruption of cellular iron metabolism in more common neurodegenerative diseases. In Specific Aim 1, we will determine the consequences of the mutation in the stability of the FTL subunit as well as in the assemble and functionality of ferritin. Detail biochemical analysis will provide the basis to understand the role of the mutation in the disease. In Specific Aim 2, we will determine the temporal and spatial patterns of ferritin deposition in brain tissues from transgenic mice and determine whether misregulation of iron metabolism in affected neurons is implicated as a cause of neurodegeneration. These studies will provide insights on basic pathological mechanisms. In Specific Aim 3, we will determine whether mutant ferritin gains a toxic function that is harmful to neurons. We will study the interaction between ferritin and nuclear proteins and the role of the ubiquitin-proteasome pathway in the abnormal accumulation of ferritin and in the pathogenesis of the disease.