Mitochondrial Fission and Fusion in Alzheimer Disease

阿尔茨海默病中的线粒体裂变和融合

基本信息

批准号：
7575733
负责人：
Xiongwei Zhu
金额：
$ 32.19万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7575733
关键词：
Address Adenoviruses Affect Alzheimer&apos s Disease Area Axon Axonal Transport Binding Brain Buffers Calcium Cells Cessation of life Chimeric Proteins Cognitive deficits Defect Dendrites Dendritic Spines Dose Dynamin Dynamin I Energy Supply Equilibrium Event Fibroblasts Functional disorder Gene Transfer Guanosine Triphosphate Phosphohydrolases Hippocampus (Brain)Human In Vitro Measures Mediating Membrane Potentials Microscopic Mitochondria Mitochondrial DNA Modeling Morphology Movement Mus Neurites Neuronal Dysfunction Neurons Organelles Pathogenesis Patients Peptide Hydrolases Physiological Play Presynaptic Terminals Process Production Proteins Regulation Role Site Synapses Synaptic Transmission Synaptic plasticity System Teratoma Testing Tg2576 Time Toxic effect Transgenic Mice Tretinoin Vertebral column base cognitive function cyclooxygenase 1 environmental enrichment for laboratory animals equilibration disorder hippocampal pyramidal neuron improved in vivo knock-down mitochondrial dysfunction mutant overexpression polarized cell public health relevance synaptogenesis

项目摘要

DESCRIPTION (provided by applicant): Early changes in AD brain include loss of synapses. AB, considered to have a central role in the pathogenesis of AD, bind to dendritic spines and cause synaptic dysfunction. However, the mechanisms responsible for AB-induced synaptic dysfunction and spine loss are not firmly established. Notably, synaptic terminals have abundant mitochondria which play an indispensable role at these sites. Along this line, mitochondrial dysfunction is an early prominent feature of AD neurons. Mitochondria are dynamic organelles that undergo continual fission and fusion events which are regulated by a machinery involving large dynamin-related GTPase that exert opposing effects, e.g., dynamin-like protein 1 (DLP1) and Fis1 for fission, and mitofusins (Mfn1 and Mfn2C) and OPA1 for fusion. These mitochondria fission and fusion proteins control not only mitochondrial number and morphology but also mitochondrial distribution and function. Indeed, defects in the mitochondrial fission/fusion balance and thus, the morphology and distribution have the potential to cause localized energy and calcium imbalance, which is especially damaging to polarized cells such as neurons, resulting in cellular dysfunction and death. Our preliminary studies suggest that the normally strict regulation of mitochondria morphology and distribution is impaired in AD neurons and fibroblasts which may be caused by differential expression of mitochondrial fission/fusion proteins induced by AB. Our central hypothesis is that AB induces mitochondrial dysfunction and synaptic abnormalities via its toxic effect on mitochondrial fission/fusion. Four aims will be pursued: Aim1) ADDLs induce mitochondrial dysfunction and synaptic abnormalities via its toxic effect on mitochondrial fission/fusion in vitro; Aim2) To Explore the Mechanisms of ADDL-induced DLP1 Reduction; Aim3) mutant PS1 causes mitochondrial abnormalities and neuronal dysfunction at least in part through its interaction with DLP1 and impaired balance in mitochondrial fission/fusion; Aim 4) DLP1 reduction underlies mitochondrial abnormalities and synaptic loss in vivo. PUBLIC HEALTH RELEVANCE: AB-caused synaptic dysfunction and spine loss is an early change and the most robust correlate of AD- associated cognitive deficits, however the underlying mechanism is not firmly established. It is known that mitochondria play an indispensable role in synaptic terminals and the balance of mitochondrial fission/fusion is critical for mitochondrial distribution and function. Our preliminary studies suggest the potential involvement of an impaired balance of mitochondrial fission/fusion in the pathogenesis of AD, in this application, we propose to investigate whether AB cause synaptic dysfunction and mitochondrial abnormalities via its toxic effect on the balance of mitochondrial fission and fusion.

描述（由申请人提供）：AD大脑的早期变化包括突触的丧失。 AB被认为在AD的发病机理中具有核心作用，与树突状刺结合并引起突触功能障碍。但是，尚未确定导致AB诱导的突触功能障碍和脊柱损失的机制。值得注意的是，突触末端具有丰富的线粒体，在这些位点起着必不可少的作用。沿着这条线，线粒体功能障碍是AD神经元的早期突出特征。线粒体是动态细胞器，经历了持续的裂变和融合事件，受涉及大型动力蛋白相关GTPase的机械调节，例如发挥相反效果，例如Dynampyin-like蛋白1（DLP1）和FIS1进行裂变，以及Mitofusins，以及Mitofusins（MFN1和MFN1和MFN1和MFN2C）和Opa1和Opa1。这些线粒体裂变和融合蛋白不仅控制线粒体数和形态，还可以控制线粒体分布和功能。实际上，线粒体裂变/融合平衡的缺陷，因此，形态和分布有可能引起局部能量和钙不平衡，这尤其损害了偏振细胞，例如神经元，从而导致细胞功能障碍和死亡。我们的初步研究表明，在AD神经元和成纤维细胞中，通常严格调节线粒体形态和分布，这可能是由于AB诱导的线粒体裂变/融合蛋白的差异表达引起的。我们的中心假设是，AB通过其对线粒体裂变/融合的毒性作用诱导线粒体功能障碍和突触异常。将追求四个目标：AIM1）ADDL通过其对线粒体裂变/体外线粒体融合的毒性作用而诱导线粒体功能障碍和突触异常； AIM2）探索ADDL诱导的DLP1减少的机制； AIM3）突变体PS1引起线粒体异常和神经元功能障碍至少部分通过与DLP1的相互作用和线粒体裂变/融合的平衡受损而受损； AIM 4）DLP1减少是线粒体异常和体内突触损失的基础。公共卫生相关性：AB引起的突触功能障碍和脊柱损失是早期的变化，并且是与认知缺陷的最牢固相关性的，但是基本机制并未牢固确定。众所周知，线粒体在突触末端起着必不可少的作用，线粒体裂变/融合的平衡对于线粒体分布和功能至关重要。我们的初步研究表明，线粒体裂变/融合在AD发病机理中的平衡受损的潜在参与，在本应用中，我们建议研究AB是否会通过其对线粒体裂变和融合平衡的毒性作用而引起突触的功能障碍和线粒体异常。