Ferritin Induced Neurodegeneration

描述（由申请人提供）：几种神经退行性疾病被认为是异常蛋白质构象的疾病。它们中的许多是由突变引起的，这些突变导致蛋白质的构象稳定性降低，从而阻止了多肽与其他亚基或稳定辅因子的正常折叠或缔合。我们描述了一种神经退行性疾病，其特征是存在与铁蛋白轻链（FTL）基因新突变相关的核内铁蛋白包涵体。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累和神经变性。我们的长期目标是确定铁蛋白包涵体形成和神经退行性过程中所涉及的结构基础和机制。这项工作具有深远的影响，超出了这个单基因疾病，因为许多其他神经退行性疾病的特点也是存在核内包涵体。此外，这些研究将增加我们对更常见的神经退行性疾病中细胞铁代谢中断的后果的理解。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理解突变在疾病中的作用提供基础。在具体目标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变性的原因有关。这些研究将提供基本的病理机制的见解。在具体目标3中，我们将确定突变铁蛋白是否获得对神经元有害的毒性功能。我们将研究铁蛋白和核蛋白之间的相互作用，以及泛素-蛋白酶体途径在铁蛋白异常积累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.