Mitochondrial Dysfunction in Down's Syndrome

唐氏综合征(DS)或21三体是最常见的出生后存活的常染色体非整倍体 智力低下的单一最常见的遗传原因。美国DS患者的数量 据估计，美国有超过35万个州。线粒体异常！功能导致选择性神经元 变性，并与包括DS在内的各种疾病有关。在这段授权期内，我们有 结果表明：1)DS神经元和星形胶质细胞存在线粒体功能障碍，导致 到异常淀粉样蛋白(I前体蛋白(APR)代谢和细胞内淀粉样蛋白(AFI)堆积；2) DS神经元、星形胶质细胞、成纤维细胞和线粒体的结构和功能均有改变。 以及3)Mfn1和Drp1的线粒体定位，这两种蛋白质是 参与DS脑和DS培养的线粒体形态和活性改变的调节 细胞。我们推测DS患者的线粒体功能障碍可能导致持续的能量缺乏。 代谢产物和慢性氧化应激是DS神经病理发展的两个关键因素 DS受试者AD的发生发展。为了进一步了解线粒体功能障碍在DS中的作用，我们 提出以下具体目标：1)表征DS的结构和功能改变 线粒体；2)表征DS患者线粒体功能障碍的分子决定因素；以及3) 分析DS患者淋巴母细胞线粒体的变化，并确定其相关性。 线粒体功能障碍是DS患者AD病理的预测因子。正常和DS脑组织样本， 将利用正常和DS皮质神经元、星形胶质细胞和成纤维细胞培养来表征 线粒体的结构和功能，并研究参与DS线粒体的分子组成 功能障碍。来自正常和DS患者的成纤维细胞和淋巴母细胞将被用于 分析外周组织中线粒体功能障碍的存在，并将使用淋巴母细胞 目的：探讨DS患者线粒体功能障碍与AD的关系。这些 实验将提供有关DS患者线粒体结构和功能的新信息，这可能是至关重要的 了解能量损伤在神经退行性疾病中的作用，并设计治疗方法。 旨在预防DS患者的神经元功能障碍和AD的神经病理进展

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 mitochondria! 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 (i precursor protein (APR) metabolism and intracellular amyloid IS (Afi) 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 neurodegenerativedisorders, and to design therapies directed to prevent neuronal dysfunction and the progression of AD neuropathology in DS patients