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.

阿尔茨海默氏病（AD）是全世界最流行、最复杂的神经退行性疾病之一。越来越多的证据表明 AD 可能与线粒体动力学的改变有关功能，表明线粒体功能障碍是 AD 干预的潜在治疗靶点然而，目前尚无治疗方法可以预防该疾病。线粒体膜靶向 AKAP 可调节线粒体动力学并有助于线粒体最近，我们小组发现1）AKAP1的丢失。触发线粒体裂变动力相关蛋白 1 (DRP1) 介导的线粒体断裂， 2) 神经元 AKAP1 解除氧化磷酸化的调节，并诱导代谢和氧化应激，通过抑制 DRP1、增强线粒体活性和阻断细胞凋亡，具有有效的神经保护特性这些结果表明 AKAP1 的调节可能具有治疗潜力。我们的初步数据表明，1）淀粉样前体蛋白。 (APP)/presnilin 1 (PS1) 突变诱导 AKAP1 显着缺失和 DRP S637 减少磷酸化，2) APP/PS1 突变导致 1 型视神经萎缩显着减少，3) APP/PS1 突变导致过氧化物酶体增殖物激活受体-γ共激活物1α显着减少，线粒体转录因子 A 表达，4) APP/PS1 突变诱导 BAX 和 BCL- 增加 xL 在年轻 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损伤 AD 视网膜神经节细胞 (RGC) 的生物能量学和结构我们将研究其结构和功能。 AD 小鼠线粒体、线粒体吞噬体形成的变化并测试 AKAP1 缺陷对 AD 小鼠线粒体、线粒体吞噬体形成的影响在目标 2 中，我们将使用 AKAP1-/- APP/PS1 小鼠研究 RGC 和海马神经元的线粒体功能障碍。确定 AKAP1 扩增对 AD RGC 的保护作用我们将研究 AKAP1 扩增是否存在。保留线粒体结构和功能，并防止树突乔木改变和突触损失我们预计这些研究将增强我们对 APP/PS1 RGC 和海马神经元的理解。 AKAP1 在 AD 发病早期如何调节线粒体网络和功能。该提案将探讨 AKAP1 扩增作为诱导视网膜和大脑神经保护的策略对抗 AD 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）

Glaucomatous optic neuropathy: Mitochondrial dynamics, dysfunction and protection in retinal ganglion cells.

青光眼性视神经病变：视网膜神经节细胞的线粒体动力学、功能障碍和保护。

DOI：
发表时间：
2023-07
期刊：
影响因子：
17.8
作者：
Ju, Won;Perkins, Guy A;Kim, Keun;Bastola, Tonking;Choi, Woo;Choi, Soo
通讯作者：
Choi, Soo

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

泛醇对青光眼神经变性和氧化应激的影响：视网膜神经节细胞存活和/或视觉功能的研究。

DOI：
发表时间：
2020-10-03
期刊：
影响因子：
0
作者：
Edwards, Genea;Lee, Yonghoon;Kim, Martha;Bhanvadia, Soham;Kim, Keun;Ju, Won
通讯作者：
Ju, Won

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

A-激酶锚定蛋白 1 在视网膜神经节细胞中的作用：神经变性和神经保护。

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

AIBP: A New Safeguard against Glaucomatous Neuroinflammation.

AIBP：预防青光眼神经炎症的新保障。

DOI：
发表时间：
2024-01-21
期刊：
影响因子：
6
作者：
Choi, Seunghwan;Choi, Soo;Bastola, Tonking;Park, Younggun;Oh, Jonghyun;Kim, Keun;Hwang, Sinwoo;Miller, Yury I;Ju, Won
通讯作者：
Ju, Won