Mitochondrial Dysfunction in Down's Syndrome

描述（由申请人提供）：唐氏综合症（DS）或21三体是最常见的常染色体非整倍体，它是最常见的智力迟钝的遗传原因。据估计，美国的退行性椎体滑移患者超过35万人。线粒体功能异常导致选择性神经元变性，并与包括退行性痴呆在内的多种疾病相关。在本研究期间，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蛋白β (Abeta)积累；2) DS神经元、星形胶质细胞、成纤维细胞和淋巴母细胞样细胞存在线粒体结构和功能改变；3)参与线粒体形态和活性调控的蛋白Mfn1和Drp1的线粒体定位在DS脑和DS培养细胞中发生改变。我们假设，退行性痴呆患者的线粒体功能障碍可能导致持续的能量产生缺陷和慢性氧化应激，这是退行性痴呆患者神经病理发展和AD发展的两个关键因素。为了进一步了解线粒体功能障碍在退行性痴呆中的作用，我们提出以下具体目标：1)表征退行性痴呆线粒体的结构和功能改变；2)研究DS线粒体功能障碍的分子决定因素；3)分析DS患者淋巴母细胞样细胞的线粒体改变，确定线粒体功能障碍与DS AD病理的相关性。将利用正常和退行性痴呆脑组织样本、正常和退行性痴呆皮层神经元、星形胶质细胞和成纤维细胞培养物来表征线粒体结构和功能，并研究退行性痴呆线粒体功能障碍的分子成分。我们将利用来源于正常人和退行性痴呆患者的成纤维细胞和成乳细胞样细胞分析外周组织是否存在线粒体功能障碍，利用成乳细胞样细胞评价退行性痴呆患者线粒体功能障碍与AD存在的关系。这些实验将提供关于退行性椎体滑移线粒体结构和功能的新信息，这可能对理解能量损伤在神经退行性疾病中的作用至关重要，并有助于设计针对预防退行性椎体滑移患者神经元功能障碍和AD神经病理进展的治疗方法。

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.