Neuroaxonal Dystrophy in Purkinje Cell Death in NPC Disease

鼻咽癌浦肯野细胞死亡中的神经轴突营养不良

• 批准号: 8526583
• 负责人: Jakub Sikora
• 金额: $ 6.11万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8526583
• 关键词: Action Potentials; Address; Adolescence; Affect; Alzheimer' s Disease; Animal Model; Antioxidants; Architecture; Ataxia; Autophagosome; Axon; Axonal Transport; Back; Behavioral; Birth; Brain; Brain Diseases; Cell Death; Cell model; Cells; Cessation of life; Child; Cholesterol; Clinical; Cyclodextrins; Defect; Development; Disease; Disease Progression; Distal; Distant; Failure; Frequencies; Functional disorder; Genes; Glycosphingolipids; Goals; Green Fluorescent Proteins; Growth Factor; Hereditary Disease; Human; In Vitro; Individual; Life; Light; Lysosomes; Miglustat; Mitochondria; Molecular; Mus; Mutation; Nerve Degeneration; Neuroaxonal Dystrophies; Neurodegenerative Disorders; Neurologic Dysfunctions; Neurons; Organelles; Parents; Pathology; Patients; Perikaryon; Pharmaceutical Preparations; Process; Proteins; Purkinje Cells; Rare Diseases; Reporting; Rest; Role; Series; Supraoptic Vertical Ophthalmoplegia; Swelling; Synapses; Synaptic Vesicles; System; Testing; Therapeutic Agents; Time; Transgenic Organisms; United States National Institutes of Health; Variant; Vesicle; base; cholesterol trafficking; design; early childhood; effective therapy; in vivo; inhibitor/antagonist; innovation; insight; motor deficit; motor impairment; mouse model; nervous system disorder; premature; prevent; promoter; protein expression; research study; trafficking

DESCRIPTION (provided by applicant): Niemann-Pick type C (NPC) disease is a cholesterol-glycosphingolipid (GSL) lysosomal storage disorder caused by defects in the NPC1 or NPC2 proteins, both of which are implicated in the trafficking of cholesterol and other compounds out of lysosomes. Most affected individuals appear normal at birth, develop behavioral changes and progressive impairment of motor and intellectual function in the first decade of life, and succumb to the disease in their second decade. Few effective treatments are currently approved and pathogenic mechanisms leading to brain dysfunction are poorly understood. One well documented feature of NPC disease that is believed to contribute to the progressive ataxia in humans and animal models is early death of Purkinje cells (PCs). But why these cells die so early has never been explained. We have proposed that PC vulnerability is a result of the formation of swellings or spheroids along the axons of these neurons. Also known as neuroaxonal dystrophy (NAD), this phenomenon has been reported in a wide variety of lysosomal diseases as well as in other commoner neurodegenerative diseases like Alzheimer's. It has been proposed to be a major contributor to clinical neurological dysfunction, yet it is rarely studied. Importantly, of all lysosomal diseases in which NAD has been described, it is NPC disease in which the scale and frequency of its occurrence is most excessive with axons of PCs being particularly susceptible. Axonal spheroids in NPC disease contain localized accumulations of mitochondria, dense bodies, tubulovesicular and endosomal/retrosomal-like profiles and possible autophagosomes, all of which are suggestive of compromise in axoplasmic transport. The goal of the current study is to use Npc1-/- mice and Npc1-/- mice with inherently fluorescent Purkinje cells (L7-GFP Npc1-/- mice) in a series of in vivo and in vitro experiments to characterize the constituents of axonal spheroids and determine the dynamic features of spheroid development throughout the course of the disease. We will test hypotheses focused on the relationship between NAD and PC death, and test the ability of several drugs (miglustat, cyclodextrins and selected antioxidants) that have shown efficacy in the NPC mouse model to modify the formation of spheroids. Understanding why NAD occurs, what its relationship is to the lysosomal defect in PCs, and what it takes to prevent or reverse its development, are critical issues for treatment of NPC disease. Moreover, understanding mechanisms that connect axonal pathology and defective axonal transport to the rest of the NPC pathogenic cascade may provide insights into more common neurological diseases like Alzheimer's where axonal pathology is increasingly recognized.

描述(申请人提供)：Niemann-Pick C型(NPC)病是一种胆固醇-鞘糖脂(GSL)溶酶体储存障碍，由NPC1或NPC2蛋白缺陷引起，这两种蛋白都与胆固醇和其他化合物从溶酶体内转运有关。大多数受影响的人在出生时看起来正常，在生命的第一个十年出现行为变化和运动和智力功能的进行性损害，并在第二个十年死于这种疾病。目前批准的有效治疗方法很少，导致脑功能障碍的致病机制也知之甚少。鼻咽癌疾病的一个有文献记载的特征被认为是导致人类和动物模型进行性共济失调的原因是浦肯野细胞(PC)的早期死亡。但这些细胞为什么会这么早死亡一直没有得到解释。我们提出PC脆弱性是沿着这些神经元轴突形成肿胀或椭圆形的结果。也被称为神经轴索营养不良(NAD)，这种现象在各种溶酶体疾病以及其他常见的神经退行性疾病如阿尔茨海默氏症中都有报道。它被认为是临床神经功能障碍的主要因素，但很少有研究。重要的是，在所有已被描述为NAD的溶酶体疾病中，鼻咽癌是其发生规模和频率最高的疾病，PC轴突尤其容易受到影响。鼻咽癌的轴突球体包括局限性的线粒体堆积、致密小体、管状突起和内体/后体样轮廓，以及可能的自噬小体，所有这些都提示轴浆运输的损害。本研究的目的是利用NPC1-/-小鼠和具有固有荧光的浦肯野细胞的NPC1-/-小鼠(L7-GFP NPC1-/-小鼠)进行一系列体内和体外实验，以表征轴突球体的成分，并确定整个疾病过程中球体发育的动态特征。我们将测试专注于NAD和PC死亡之间关系的假设，并测试几种药物(米卢斯特、环糊精和选定的抗氧化剂)在NPC小鼠模型中改变球体形成的能力。了解NAD发生的原因，它与PC中溶酶体缺陷的关系，以及如何防止或逆转其发展，是治疗鼻咽癌疾病的关键问题。此外，了解轴突病理和轴突运输缺陷与鼻咽癌病理性级联反应的其他部分之间的联系机制，可能会为阿尔茨海默病等更常见的神经疾病提供见解，因为在阿尔茨海默氏症中，轴突病理得到了越来越多的认识。