Targeting Mitochondrial Fission for Neuroprotection in Diabetic Neuropathy

靶向线粒体裂变对糖尿病神经病变的神经保护作用

基本信息

批准号：
10159246
负责人：
STEFAN STRACK
金额：
$ 41.96万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10159246
关键词：
A kinase anchoring protein Address Affect Afferent Neurons Alzheimer&apos s Disease Apoptosis Autosomal Dominant Optic Atrophy Axon Back Biochemistry Bioenergetics Biogenesis Calcineurin Charcot-Marie-Tooth Disease Complications of Diabetes Mellitus Cyclic AMP-Dependent Protein Kinases Diabetes Mellitus Diabetic Neuropathies Diabetic mouse Dynamin Enzymes Equilibrium Etiology Event Face Failure Family Generations Guanosine Triphosphate Phosphohydrolases High Fat Diet Homeostasis Huntington Disease Image Impairment Incidence Infarction Inherited Injury Insulin-Dependent Diabetes Mellitus Ischemic Stroke Knock-out Knockout Mice Lead Light Link Mechanics Mediating Metabolism Mitochondria Modeling Mutation Natural regeneration Nerve Neural Conduction Neurodegenerative Disorders Neurologic Neurons Non-Insulin-Dependent Diabetes Mellitus Numbness OPA1 gene Obesity Outer Mitochondrial Membrane PPP3CA gene Palliative Care Pathogenesis Pathogenicity Peripheral Peripheral Nerves Peripheral Nervous System Diseases Phosphoric Monoester Hydrolases Phosphorylation Site Population Preparation Protein Dephosphorylation Protein Isoforms Protein phosphatase Proteins Quality Control Quality of life RNA Splicing Reactive Oxygen Species Resistance Role Scanning Electron Microscopy Sensory Shapes Signal Transduction Site Skin Spinal Ganglia Streptozocin Stroke Structure Testing Transcription Factor AP-1 Variant Viral axon regeneration axonal degeneration calcineurin phosphatase chronic pain comorbidity cytochrome c density diabetic diabetic patient electron tomography hereditary blindness imaging approach improved in vivo in vivo imaging innovation leptin receptor mitochondrial metabolism mouse model mutant nerve supply nervous system disorder neuroprotection novel novel therapeutic intervention oxidative damage pandemic disease patient population prevent recruit sciatic nerve socioeconomics targeted treatment trafficking type I and type II diabetes

项目摘要

Project Summary / Abstract Presenting with chronic pain or loss of sensation, peripheral diabetic neuropathy (PDN) is a debilitating comorbidity of diabetes that affects at least half the diabetic patient population. Since only palliative treatments are available, there is an urgent need for therapies that prevent or reverse the “dying back” degeneration of peripheral axons in PDN. Recent evidence suggests that diabetes compromises mitochondrial structure and function in sensory neurons. However, the underlying mechanisms are unknown. Mitochondrial shape is controlled by opposing fission and fusion events. Mutations in mitochondrial fusion enzymes cause neurological disorders that present similarly to neurological complications in diabetic patients. Specifically, mitofusin-2 mutations result in Charcot-Marie-Tooth disease type 2A, a peripheral neuropathy characterized by primary axon degeneration, while mutations in Opa1 cause dominant optic atrophy, the most common form of hereditary blindness. The mitochondrial fission enzyme dynamin-related protein 1 (Drp1) is activated by dephosphorylation of a highly conserved inhibitory PKA phosphorylation site. Two phosphatases target this site to promote mitochondrial fission, the Ca2+-dependent phosphatase calcineurin and a neuron-specific and mitochondria- localized isoform of protein phosphatase 2A containing the Bβ2 regulatory subunit (PP2A/Bβ2). We generated a mouse knock-out (KO) of Bβ2 and found elongated mitochondria in neurons, consistent with deletion of a Drp1 activator. Bβ2 KO results in a striking reduction in infarct volume following ischemic stroke, indicating that mitochondrial elongation is neuroprotective. Conversely, knocking out A Kinase Anchoring Protein 1 (AKAP1), the protein that recruits PKA to the outer mitochondrial membrane to maintain Drp1 in a phosphorylated and inhibited state, causes mitochondrial fragmentation and exacerbates stroke injury. Supported by preliminary evidence that Bβ2 KO mice are resistant to peripheral neuropathy in both type-1 and type-2 diabetes models, the present proposal seeks proof-of-concept evidence for Bβ2 (and other, as yet undiscovered, neuron-specific Drp1 activators) as a drug target for the treatment of PDN. We further propose to investigate how diabetes causes mitochondrial fragmentation in sensory neurons and how inhibiting mitochondrial fragmentation protects peripheral axons in diabetes. Using new mouse models and innovative in vivo imaging approaches, we will test the overarching hypothesis that dysregulation of the mitochondrial fission/fusion equilibrium contributes to the pathogenesis of diabetic neuropathy, and that inhibition of Drp1- dependent mitochondrial fission provides neuroprotection via improvement of mitochondrial metabolism, reduction of ROS, modulation of mitochondrial Ca2+ transport and enhanced regeneration of sensory axons. We anticipate that these studies will shed light on PDN etiology, suggest new therapeutic strategies, and thus help improve quality of life for a rapidly growing diabetic population.

项目摘要 /摘要表现出慢性疼痛或感觉丧失，外周糖尿病神经病（PDN）是令人衰弱的糖尿病的合并症至少影响糖尿病患者人群的一半。由于只有姑息治疗可用，迫切需要疗法，以防止或扭转 PDN中的外围轴突。最近的证据表明，糖尿病会损害线粒体结构和感觉神经元的功能。但是，基本机制尚不清楚。线粒体形状由相反的裂变和融合事件控制。线粒体突变融合酶引起的神经系统疾病，与糖尿病的神经系统并发症相似患者。特别是，丝利法蛋白-2突变导致charcot-marie-tooth疾病2A型，一种外周以初级轴突变性为特征的神经病变，而OPA1中的突变引起显性视神经萎缩，是遗传失明的最常见形式。线粒体裂变酶动力蛋白相关蛋白1（DRP1）通过去磷酸化激活高度保守的抑制性PKA磷酸化位点。两个磷酸酶靶向该地点以促进线粒体裂变，Ca2+依赖性磷酸酶钙调蛋白以及神经元特异性和线粒体含有Bβ2调节亚基（PP2A/Bβ2）的蛋白质磷酸酶2a的局部同工型。我们生成了 Bβ2的小鼠敲除（KO），并在神经元中发现线粒体细长，与A的缺失一致 DRP1激活剂。 Bβ2KO导致缺血性中风后的梗塞体积降低，表明线粒体伸长是神经保护性的。相反，拆除锚定蛋白1（AKAP1）的激酶，将PKA募集到外部线粒体膜的蛋白质维持磷酸化和抑制状态，导致线粒体碎裂并加剧卒中损伤。在初步证据的支持下，Bβ2KO小鼠在两者中都对周围神经病有抗性 1型和2型糖尿病模型，本提案寻求Bβ2的概念证据证据（以及其他，尚未发现的神经特异性DRP1激活剂）作为PDN治疗的药物靶标。我们进一步提出研究糖尿病如何引起感觉神经元中线粒体碎片的建议以及如何抑制线粒体碎片化可保护糖尿病中的外围轴突。使用新的鼠标模型和创新体内成像方法，我们将测试线粒体失调的总体假设裂变/融合平衡有助于糖尿病神经病的发病机理，并抑制DRP1- 依赖性线粒体裂变通过改善线粒体代谢，可提供神经保护作用， ROS的还原，线粒体Ca2+转运的调节以及增强感觉轴突的再生。我们预计这些研究将阐明PDN病因，提出新的治疗策略，从而提出了新的治疗策略，从而提出了新的治疗策略帮助改善快速增长的糖尿病人群的生活质量。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Stay or go? Neuronal activity in medial frontal cortex during a voluntary tactile preference task in head-fixed mice.

DOI：
10.1016/j.ceca.2021.102388
发表时间：
2021-06
期刊：
Cell calcium
影响因子：
4
作者：
Keyes AL;Kim YC;Bosch PJ;Usachev YM;Aldridge GM
通讯作者：
Aldridge GM

Mitochondrial calcium uniporter b deletion inhibits platelet function and reduces susceptibility to arterial thrombosis.

线粒体钙单向转运蛋白 b 缺失会抑制血小板功能并降低动脉血栓形成的易感性。

DOI：
10.1016/j.jtha.2023.04.002
发表时间：
2023
期刊：
Journal of thrombosis and haemostasis : JTH
影响因子：
0
作者：
Ghatge,Madankumar;Nayak,ManasaK;Flora,GaganD;Kumskova,Mariia;Jain,Aditi;Patel,RakeshB;Lin,Zhihong;Usachev,YuriyM;Chauhan,AnilK
通讯作者：
Chauhan,AnilK

The complement cascade in the regulation of neuroinflammation, nociceptive sensitization, and pain.