Mitochondrial Dysfunction in Down's Syndrome

唐氏综合症的线粒体功能障碍

• 批准号: 7039274
• 负责人: JORGE A BUSCIGLIO
• 金额: $ 19.83万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7039274
• 关键词: Alzheimer' s disease; Downs syndrome; bioenergetics; biomarker; comorbidity; mitochondrial disease /disorder; nervous system disorder epidemiology; neural degeneration; neuropathology; oxidative stress; pathologic process; tissue /cell culture

DESCRIPTION (provided by applicant): Down's syndrome (DS) or trisomy 21 is the most common autosomal aneuploidy that survives birth and it is the single most frequent genetic cause of mental retardation. The number of DS patients in the United States is estimated to be more than 350,000. Abnormal mitochondrial function cause selective neuronal degeneration and is associated with a variety of disorders including DS. During this grant period, we have obtained results indicating that: 1) mitochondrial dysfunction exist in DS neurons and astrocytes, which leads to aberrant amyloid a precursor protein (APR) metabolism and intracellular amyloid beta (Abeta) accumulation; 2) there are mitochondrial structural and functional alterations in DS neurons, astrocytes, fibroblast and lymphoblastoid cells; and 3) the mitochondrial localization of Mfn1 and Drp1, which are proteins that participate in the regulation of mitochondrial morphology and activity is altered in DS brains and DS cultured cells. We hypothesize that mitochondrial dysfunction in DS may lead to a persistent deficit in energy production and chronic oxidative stress, two critical factors in the development of DS neuropathology and the development of AD in DS subjects. To further understand the role of mitochondrial dysfunction in DS, we propose the following specific aims: 1) to characterize the structural and functional alterations in DS mitochondria; 2) to characterize the molecular determinants of mitochondrial dysfunction in DS; and 3) to analyze mitochondrial alterations in limphoblastoid cells of DS patients, and to determine the relevance of mitochondrial dysfunction as a predictor of AD pathology in DS. Normal and DS brain tissue samples, normal and DS cortical neurons, astrocytes and fibroblast cultures will be utilized to characterize mitochondrial structure and function and to study the molecular components involved in DS mitochondrial dysfunction. Fibroblast and limphoblastoid cells derived from normal and DS subjects will be utilized to analyze the existence of mitochondrial dysfunction in peripheral tissues, and limphoblastoid cells will be used to evaluate the relation between mitochondrial dysfunction and the presence of AD in DS subjects. These experiments will provide novel information on mitochondrial structure and function in DS that may be critical to understand the role of energy impairment in neurodegenerative disorders, and to design therapies directed to prevent neuronal dysfunction and the progression of AD neuropathology in DS patients.

描述（由申请人提供）：唐氏综合症（DS）或三体疾病是最常见的常染色体非整倍性，它可以生存出生，并且是智力低下的最常见遗传原因。美国的DS患者人数估计超过350,000。线粒体功能异常引起选择性神经元变性，并与包括DS在内的多种疾病有关。在此赠款期间，我们获得的结果表明：1）在DS神经元和星形胶质细胞中存在线粒体功能障碍，这导致异常淀粉样蛋白A前体蛋白（APR）代谢和细胞内淀粉样蛋白β（ABETA）的积累； 2）DS神经元，星形胶质细胞，成纤维细胞和淋巴母细胞的线粒体结构和功能改变； 3）MFN1和DRP1的线粒体定位，它们是参与线粒体形态和活性调节的蛋白质，在DS大脑和DS培养的细胞中会改变。我们假设DS中的线粒体功能障碍可能导致能量产生和慢性氧化应激的持续缺陷，DS神经病理学发展的两个关键因素以及DS受试者中AD的发展。为了进一步了解线粒体功能障碍在DS中的作用，我们提出以下特定目的：1）表征DS线粒体中的结构和功能改变； 2）表征DS中线粒体功能障碍的分子决定因素； 3）分析DS患者林型细胞细胞中线粒体的改变，并确定线粒体功能障碍作为DS中AD病理学的预测指标的相关性。正常和DS脑组织样品，正常和DS皮质神经元，星形胶质细胞和成纤维细胞培养物将用于表征线粒体结构和功能，并研究涉及DS线粒体功能障碍的分子成分。衍生自正常和DS受试者的成纤维细胞和成纤维细胞细胞将用于分析外周组织中线粒体功能障碍的存在，并且将使用林型细胞细胞来评估线粒体功能障碍与DS受试者AD的存在之间的关系。这些实验将提供有关DS中线粒体结构和功能的新信息，这对于了解能量障碍在神经退行性疾病中的作用可能至关重要，并设计针对DS患者中神经元功能障碍和AD神经病理学进展的疗法。