Role of PS1 in Mitochondria Dynamics and Mitochondria Function

PS1 在线粒体动力学和线粒体功能中的作用

• 批准号: 8636966
• 负责人: Xinglong Wang
• 金额: $ 7.93万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8636966
• 关键词: Address; Affect; Alzheimer' s Disease; Brain; Brain region; Cells; Data; Dementia; Disease; Elderly; Equilibrium; Event; Genes; Hippocampus (Brain); Human; Investigation; Knock-out; Lead; Measures; Mediating; Mitochondria; Morphology; Movement; Mus; Mutation; Nerve Degeneration; Neurofibrillary Tangles; Neuronal Dysfunction; Neurons; Organelles; Outcome; Pathogenesis; Physiological; Regulation; Research; Role; Senile Plaques; Site; Synapses; System; Therapeutic Intervention; Time; base; early onset; familial Alzheimer disease; insight; mitochondrial dysfunction; mutant; neuron loss; new therapeutic target; novel; postnatal; presenilin; prevent; public health relevance; pup; tool

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the leading cause of dementia in the elderly, characterized by neurofibrillary tangles, senile plaques and a progressive loss of neuronal cells in selective brain regions. Mitochondrial dysfunction is a prominent and early feature of the disease, although the underlying mechanism is still not clear. Mitochondria are dynamics organelles that undergo continual fission and fusion events which serve crucial physiological function. Our recent studies demonstrated that an altered balance in mitochondrial fission and fusion was likely an important mechanism leading to mitochondrial and synaptic/neuronal dysfunction in AD brain. Mutations in presenilins (PS) cause early-onset familial form of AD (FAD). PS1 is found in mitochondria and mutant PS1 affects mitochondrial function and transport. Our preliminary studies revealed that PS1 knockout (KO) primary neurons demonstrated significant changes in mitochondria morphology, distribution and movement which could be prevented by co-expression of wild-type PS1, but not FAD-causing PS1 mutant, suggesting that presenilins are involved in the regulation of mitochondrial dynamics which may be impaired by PS1 FAD mutations. Most importantly we found that PS1 physically interacted with DLP1, a key regulator of both mitochondrial fission and distribution. These studies suggest that a detailed investigation into the potential role of PS1 in mitochondrial function and dynamics is warranted. Based on our preliminary studies, we hypothesize that FAD-associated PS1 mutants cause impaired regulation of mitochondrial dynamics through specific interaction with DLP1 which causes mitochondrial dysfunction and redistribution which adversely affects neuronal functions including causing synaptic abnormalities in AD. To begin to address this hypothesis, the following specific aims will be pursued: 1) to determine the effect of FAD-associated PS1 mutants on mitochondria dynamics; 2) to determine whether PS1-DLP1 interaction mediates the effects of FAD-associated PS1 mutants on mitochondrial dynamics.

描述（由申请人提供）：阿尔茨海默氏病（AD）是老年人痴呆的主要原因，其特征是神经原纤维缠结、老年斑和选择性大脑区域神经元细胞的逐渐丧失。线粒体功能障碍是该疾病的一个突出的早期特征，尽管其潜在机制仍不清楚。线粒体是动态细胞器，经历持续的裂变和融合事件，具有重要的生理功能。我们最近的研究表明，线粒体裂变和融合的平衡改变可能是导致 AD 大脑中线粒体和突触/神经元功能障碍的重要机制。早老素 (PS) 突变会导致早发家族型 AD (FAD)。 PS1 存在于线粒体中，突变的 PS1 会影响线粒体功能和运输。我们的初步研究表明，PS1 敲除 (KO) 原代神经元表现出线粒体形态、分布和运动的显着变化，这种变化可以通过野生型 PS1 的共表达来预防，但不能通过引起 FAD 的 PS1 突变体来阻止，这表明早老素参与了线粒体动力学的调节，而线粒体动力学可能会受到 PS1 FAD 突变的损害。最重要的是，我们发现 PS1 与 DLP1 发生物理相互作用，DLP1 是线粒体裂变和分布的关键调节因子。这些研究表明，有必要对 PS1 在线粒体功能和动力学中的潜在作用进行详细研究。基于我们的初步研究，我们假设 FAD 相关的 PS1 突变体通过与 DLP1 的特异性相互作用导致线粒体动力学调节受损，从而导致线粒体功能障碍和重新分布，从而对神经元功能产生不利影响，包括导致 AD 中的突触异常。为了开始解决这一假设，将追求以下具体目标：1）确定 FAD 相关 PS1 突变体对线粒体动力学的影响； 2)确定PS1-DLP1相互作用是否介导FAD相关PS1突变体对线粒体动力学的影响。

项目成果

The ALS disease-associated mutant TDP-43 impairs mitochondrial dynamics and function in motor neurons.

• DOI: 10.1093/hmg/ddt319
• 发表时间: 2013-12
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Wenzhang Wang;Li Li-Li;Wen‐lang Lin;D. Dickson;L. Petrucelli;Teng Zhang;Xinglong Wang