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: 8490511
• 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/8490511
• 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）：尼曼-匹克 C 型（NPC）疾病是一种由 NPC1 或 NPC2 蛋白缺陷引起的胆固醇-鞘糖脂（GSL）溶酶体贮积症，这两种蛋白都与胆固醇和其他化合物从溶酶体中的运输有关。大多数受影响的个体在出生时表现正常，在生命的第一个十年中出现行为变化以及运动和智力功能的渐进性损伤，并在第二个十年中死于该疾病。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知之甚少。 NPC 疾病的一项有据可查的特征是浦肯野细胞 (PC) 的早期死亡，据信该特征会导致人类和动物模型中的进行性共济失调。但为什么这些细胞死得这么早还没有得到解释。我们提出 PC 脆弱性是由于这些神经元的轴突形成肿胀或球体的结果。这种现象也称为神经轴索营养不良（NAD），已在多种溶酶体疾病以及其他常见神经退行性疾病（如阿尔茨海默病）中报道过。它被认为是临床神经功能障碍的一个主要因素，但很少有人对其进行研究。重要的是，在所有已描述的 NAD 溶酶体疾病中，鼻咽癌疾病的发生规模和频率最为严重，其中 PC 的轴突特别容易受到影响。鼻咽癌疾病中的轴突球体含有线粒体、致密体、管泡和内体/逆转录体样特征以及可能的自噬体的局部积累，所有这些都表明轴浆运输受到损害。目前研究的目标是利用Npc1-/-小鼠和具有固有荧光浦肯野细胞的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。我们将测试侧重于 NAD 和 PC 死亡之间关系的假设，并测试几种药物（米格司他、环糊精和选定的抗氧化剂）的能力，这些药物已在 NPC 小鼠模型中显示出改变球状体形成的功效。了解 NAD 发生的原因、它与 PC 中溶酶体缺陷的关系以及如何预防或逆转其发展，是治疗 NPC 疾病的关键问题。此外，了解将轴突病理学和轴突运输缺陷与 NPC 致病级联的其余部分联系起来的机制可能有助于了解更常见的神经系统疾病，例如阿尔茨海默病，其中轴突病理学越来越得到认可。