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（由申请人提供）：Niemann-Pick型C（NPC）疾病是一种胆固醇 - 糖脂脂（GSL）溶酶体储存障碍，由NPC1或NPC2蛋白缺陷引起，它们与胆固醇和其他化合物的运输和其他化合物相关。大多数受影响的人在出生时看起来正常，在生命的头十年中发展行为变化以及运动和智力功能的逐渐损害，并在第二个十年中屈服于该疾病。目前很少有有效的治疗方法被批准，导致脑功能障碍的致病机制知之甚少。 NPC疾病的一个有据可查的特征被认为有助于人类和动物模型的进行性共济失调，这是Purkinje细胞（PC）的早期死亡。但是，为什么这些细胞死亡这么早就没有被解释过。我们已经提出，PC脆弱性是沿这些神经元轴突形成或球体形成的结果。又称这种现象也称为神经乳律营养不良（NAD），已经报道了多种溶酶体疾病以及其他更常见的神经退行性疾病（如阿尔茨海默氏病）。有人认为它是引起临床神经功能障碍的主要贡献者，但很少对其进行研究。重要的是，在描述了NAD的所有溶酶体疾病中，正是NPC疾病中，其发生的尺度和频率最多，PC轴突特别易感。 NPC疾病中的轴突球体含有线粒体，密集体，肾小管和内体/后类样的轮廓以及可能的自噬体的局部积累，所有这些都暗示了轴质运输中的损害。当前研究的目的是在一系列体内和体外实验中，使用固有荧光的Purkinje细胞（L7-GFP NPC1 - / - 小鼠）使用NPC1 - / - / - / - 小鼠，以表征整个Spheroid综合症的动态特征。我们将测试集中于NAD和PC死亡之间关系的假设，并测试几种药物（Miglustat，环糊精和所选抗氧化剂）的能力，这些药物在NPC小鼠模型中显示出有效性，以改变球形的形成。了解为什么会发生NAD，其与PC中溶酶体缺陷的关系以及预防或扭转其发育所需的关系是治疗NPC疾病的关键问题。此外，了解将轴突病理学和有缺陷的轴突转运与NPC其他病原级联反应连接的机制可以提供对更常见的神经系统疾病（如阿尔茨海默氏病）越来越多地识别出轴突病理的洞察力。