Defining the role of brain iron dysregulation in Huntington's disease

描述（由申请人提供）：该项目的主要目标是验证我们的核心假设，即亨廷顿病（HD）的脑铁积累促进疾病的发生和进展。HD是一种最终致命的神经退行性疾病，仅在美国就有大约3万人患有这种疾病，目前尚无有效的治疗方法。亨廷顿基因中的CAG-repeat扩增导致多谷氨酰胺扩增突变亨廷顿蛋白的表达，导致一系列下游效应，包括能量失调、谷氨酸异常信号、铁升高、氧化和亚硝化应激，最终导致神经元变性和丧失。越来越多的证据表明，铁稳态失调与HD以及ALS、帕金森病和阿尔茨海默病的发病机制有关。然而，令人惊讶的是，对于HD是如何发生的，以及铁调节失调在多大程度上导致了整个疾病过程，我们知之甚少。我们首次表明，铁在小鼠HD纹状体和皮质神经元中积累，这些区域有明显的变性。淀粉样前体蛋白（APP）在神经元铁输出中起关键作用。我们发现APP及其铁出口氧化铁酶活性显著降低。我们也有

DESCRIPTION (provided by applicant): The primary goal of this project is to test our core hypothesis that brain iron accumulation in Huntington's disease (HD) promotes disease onset and progression. HD is an ultimately fatal neurodegenerative disease that afflicts about 30000 people in the USA alone and has no effective treatments. CAG-repeat expansion within the huntingtin gene results in expression of a polyglutamine-expanded mutant huntingtin protein leading to a number of downstream effects including energetic dysregulation, aberrant glutamate signaling, iron elevation, oxidative and nitrosative stress, and eventually neuronal degeneration and loss. There is growing evidence that dysregulation of iron homeostasis contributes to the pathogenesis of HD as well as ALS, Parkinson's and Alzheimer's diseases. Surprisingly however, little is known about how this occurs in HD and to what degree iron dysregulation contributes to the overall disease process. We have shown for the first time that iron accumulates in mouse HD striatal and cortical neurons, regions where there is significant degeneration. Amyloid precursor protein (APP) has a key role in neuronal iron export. We show significantly decreased levels of APP as well as its iron export ferroxidase activity. We have also demonstrated elevated iron in an inducible mutant huntingtin expressing cell line and shown that nNOS inhibition reverses this. These interesting and important findings point to a link between nitric oxide, APP and iron in HD and form the basis for the proposed studies. Aim 1 will test the hypothesis that nitrosative stress mediates decreased APP protein levels resulting in elevated iron which potentiates neurodegeneration. In Aim 1A we will determine the effect of genetic modulation of APP on outcomes in HD models. In Aim 1B we study the effects of nNOS inhibition on HD outcomes including APP and iron. We will use transgenic and full-length mutant huntingtin mouse models as well as HD cell lines and primary neuron cultures. Aim 2 will test the hypothesis that nutritionally relevant elevated iron intake potentiates brain iron accumulation and neurodegeneration in HD mice. The studies will provide important insights into mechanisms of iron dysregulation in HD. Findings will determine the extent to which dysregulated iron in HD brain potentiates disease; they may validate APP as a novel therapeutic target as well as provide insight into modulatory effects of dietary iron in HD.