Role of PS1 in Mitochondria Dynamics and Mitochondria Function

描述（由申请人提供）：阿尔茨海默病（AD）是老年人痴呆的主要原因，其特征是神经原纤维缠结、老年斑和选择性脑区神经元细胞的进行性损失。线粒体功能障碍是该疾病的一个突出的早期特征，尽管其潜在的机制尚不清楚。线粒体是一种动态的细胞器，它经历不断的裂变和融合事件，具有重要的生理功能。我们最近的研究表明，线粒体分裂和融合平衡的改变可能是导致AD脑线粒体和突触/神经元功能障碍的重要机制。早老素（PS）突变导致早发性家族性AD （FAD）。PS1存在于线粒体中，突变体PS1影响线粒体功能和运输。我们的初步研究表明，PS1敲除（KO）原代神经元在线粒体形态、分布和运动方面表现出显著的变化，这些变化可以被野生型PS1共同表达所阻止，但不会被FAD引起的PS1突变所阻止，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被PS1 FAD突变所损害。最重要的是，我们发现PS1在物理上与DLP1相互作用，DLP1是线粒体分裂和分布的关键调节器。这些研究表明，对PS1在线粒体功能和动力学中的潜在作用进行详细的调查是必要的。根据我们的初步研究，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，DLP1导致线粒体功能障碍和再分布，从而对神经元功能产生不利影响，包括导致AD患者的突触异常。开始解决这一假设，将追求以下具体目标：1)确定的影响

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.