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Mitochondrial Protection in Glaucomatous Optic Neuropathy

青光眼视神经病变中的线粒体保护

基本信息

批准号：
10711446
负责人：
WONKYU JU
金额：
$ 39.5万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10711446
关键词：
A kinase anchoring protein Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Amyloid beta-Protein Precursor Apoptotic Autosomal Dominant Optic Atrophy BAX gene BCL2L1 gene Bioenergetics Brain Calcium Cell Death Complex Data Disease Dynamin Functional disorder Glaucoma Hippocampus Homeostasis Impairment Induced Mutation Intervention Link Mediating Metabolic stress Mitochondria Mus Nerve Degeneration Neurodegenerative Disorders Neurons Outer Mitochondrial Membrane Oxidative Phosphorylation Oxidative Stress PPAR gamma Pathogenesis Phosphorylation Property Proteins Retina Retinal Ganglion Cells Signal Pathway Signal Transduction Structure Synapses Testing Therapeutic infancy mitochondrial dysfunction mtTF1 transcription factor neuroprotection optic nerve disorder preservation prevent protective effect therapeutic target

项目摘要

Alzheimer’s disease (AD) is one of the most prevalent and complex neurodegenerative diseases worldwide. Accumulating evidence indicates that AD is potentially linked to alterations of mitochondrial dynamics and function, indicating that mitochondrial dysfunction is a potential therapeutic target for AD intervention and treatment. However, no current therapies prevent the disease. A-kinase anchoring protein 1 (AKAP1) is an outer mitochondrial membrane-targeted AKAP that regulates mitochondrial dynamics and contributes to mitochondrial network, bioenergetics and calcium homeostasis. Recently, our group has discovered that 1) loss of AKAP1 triggers mitochondrial fission dynamin-related protein 1 (DRP1)-mediated mitochondrial fragmentation, deregulates oxidative phosphorylation, and induces metabolic and oxidative stress, 2) neuronal AKAP1 has potent neuroprotective properties by inhibiting DRP1, enhancing mitochondrial activity, and blocking apoptotic cell death. These results suggest the possibility that modulation of AKAP1 has therapeutic potential in mitochondrial dysfunction and neurodegeneration. Our preliminary data showed that 1) amyloid precursor protein (APP)/presnilin 1 (PS1) mutation induces a significant loss of AKAP1 and reduction of DRP S637 phosphorylation, 2) APP/PS1 mutation induces a significant reduction of optic atrophy type 1, 3) APP/PS1 mutation induces a significant reduction of peroxisome proliferator-activated receptor-gamma coactivator 1α and mitochondrial transcription factor A expression, and 4) APP/PS1 mutation induces an increase of BAX and BCL- xL expression in the retina of young APP/PS1 mice. Based on these findings, our proposal has two specific aims. In Aim 1, we will determine whether AKAP1 deficiency contributes to the impairment of mitochondrial bioenergetics and structure in AD retinal ganglion cells (RGCs). We will investigate structural and functional changes of mitochondria, mitophagosome formation in AD mice and test the effect of AKAP1 deficiency on mitochondrial dysfunction in RGCs and hippocampal neurons using AKAP1-/- APP/PS1 mice. In Aim 2, we will determine the protective effect of AKAP1 amplification on AD RGCs. We will investigate if AKAP1 amplification preserves mitochondrial structure and function and prevents dendritic arbor alteration and synaptic losses in APP/PS1 RGCs and hippocampal neurons. We anticipate that these studies will enhance our understanding of how AKAP1 regulates mitochondrial networks and functions in the early stage of AD pathogenesis. Also, this proposal will probe AKAP1 amplification as a strategy to induce neuroprotection in both the retina and brain against AD and related dementias.

阿尔茨海默病是世界范围内最常见、最复杂的神经退行性疾病之一。越来越多的证据表明，阿尔茨海默病可能与线粒体动力学和提示线粒体功能障碍是AD干预和治疗的潜在靶点。治疗。然而，目前还没有任何治疗方法可以预防这种疾病。A-激酶锚定蛋白1(AKAP1)是一种外源蛋白线粒体膜靶向AKAP，调节线粒体动力学并对线粒体有贡献网络、生物能量学和钙稳态。最近，我们团队发现1)AKAP1的丢失触发线粒体分裂动力蛋白相关蛋白1(Drp1)介导的线粒体碎裂，解除对氧化磷酸化的调控，诱导代谢和氧化应激，2)神经元AKAP1 通过抑制Drp1、增强线粒体活性和阻断细胞凋亡而具有强大的神经保护作用细胞死亡。这些结果表明，AKAP1的调节可能在急性髓细胞白血病中具有治疗潜力线粒体功能障碍和神经变性。我们的初步数据显示：1)淀粉样前体蛋白 (APP)/Presnlin 1(PS1)突变导致AKAP1显著丢失和DRPS637减少磷酸化，2)APP/PS1突变诱导1型视神经萎缩显著减少，3)APP/PS1 突变诱导过氧化物体增殖物激活受体-γ共激活因子1α显著降低线粒体转录因子A的表达，以及4)APP/PS1突变诱导bax和bcl1的表达增加。 XL在幼年APP/PS1小鼠视网膜中的表达。基于这些发现，我们的建议有两个具体目标。在目标1中，我们将确定AKAP1缺乏是否会导致线粒体的损伤阿尔茨海默病视网膜神经节细胞的生物能量学和结构。我们将研究结构和功能阿尔茨海默病小鼠线粒体、线粒体、吞噬小体的变化及AKAP1缺乏对其的影响 AKAP1-/-APP/PS1小鼠视网膜神经节细胞和海马神经元线粒体功能障碍。在目标2中，我们将检测AKAP1扩增对AD视网膜节细胞的保护作用。我们将调查AKAP1扩增是否保护线粒体结构和功能，防止树突状突起改变和突触丢失 APP/PS1 RGCs和海马神经元。我们预计，这些研究将加深我们对 AKAP1在AD发病早期如何调控线粒体网络和功能还有，这个提案将探索AKAP1扩增作为诱导视网膜和大脑神经保护的一种策略抗阿尔茨海默病和相关痴呆症。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Role of A-Kinase Anchoring Protein 1 in Retinal Ganglion Cells: Neurodegeneration and Neuroprotection.

DOI：
10.3390/cells12111539
发表时间：
2023-06-03
期刊：
CELLS
影响因子：
6
作者：
Bastola, Tonking;Perkins, Guy A.;Kim, Keun-Young;Choi, Seunghwan;Kwon, Jin-Woo;Shen, Ziyao;Strack, Stefan;Ju, Won-Kyu
通讯作者：
Ju, Won-Kyu

Effect of Ubiquinol on Glaucomatous Neurodegeneration and Oxidative Stress: Studies for Retinal Ganglion Cell Survival and/or Visual Function.