Mitochondrial Dysfunction in Down's Syndrome

描述(申请人提供)：唐氏综合征(DS)或21三体是出生后存活的最常见的常染色体非整倍体，也是导致智力低下的最常见的遗传原因。据估计，美国DS患者的数量超过35万人。线粒体功能异常会导致选择性神经元变性，并与包括DS在内的多种疾病有关。在此期间，我们获得的结果表明：1)DS神经元和星形胶质细胞存在线粒体功能障碍，导致淀粉样蛋白A前体蛋白(APR)代谢异常和细胞内淀粉样β蛋白(Abeta)积聚；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发生变化；3)参与调节线粒体形态和活性的Mfn1和DRp1在DS脑和DS培养细胞中的定位发生变化。我们推测DS患者的线粒体功能障碍可能导致持续的能量产生不足和慢性氧化应激，这两个因素在DS患者的神经病理学和AD的发生发展中起关键作用。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线粒体的结构和功能改变；2)表征DS患者线粒体功能障碍的分子决定因素；3)分析DS患者成纤维细胞中线粒体的改变，并确定线粒体功能障碍与DS的AD病理的相关性。将利用正常和DS脑组织样本、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线粒体功能障碍的分子成分。来自正常和DS患者的成纤维细胞和成纤维细胞将被用来分析周围组织中线粒体功能障碍的存在，而成纤维细胞细胞将被用来评估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，这些信息可能对于了解能量损伤在神经退行性疾病中的作用以及设计针对DS患者神经元功能障碍和AD神经病理进展的治疗方案至关重要。

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.