Synaptic Dysfunction and Energy Failure in Parkinson's Disease

帕金森病的突触功能障碍和能量衰竭

• 批准号: 10504365
• 负责人: HUI ZHANG
• 金额: $ 42.91万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10504365
• 关键词: ATP Synthesis Pathway; Address; Affect; Age of Onset; Axon; Behavioral; Biochemical; Biological Assay; Brain; Buffers; Calcium; Characteristics; Corpus striatum structure; Data; Defect; Dopamine; Early treatment; Electron Transport; Electrophysiology (science); Event; Failure; Fluorescence; Functional disorder; Genes; Genetic; Haplotypes; Homeostasis; Human; Image; Impairment; In Vitro; Isradipine; Kinesin; Knock-out; LRRK2 gene; Measures; Mediating; Mitochondria; Morphology; Motor; Mus; Mutation; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathogenesis; Pathogenicity; Pathologic; Pathology; Phenotype; Preparation; Proteins; Respiration; Role; Slice; Substantia nigra structure; Symptoms; Synapses; Testing; Therapeutic Intervention; Transgenic Mice; Transportation; Virus; age group; age related; axonal degeneration; axonopathy; dopaminergic neuron; experimental study; hyperphosphorylated tau; in vivo; insight; knock-down; mitochondrial dysfunction; mouse genetics; mouse model; mutant; neurochemistry; neurotransmission; neurotransmitter release; optogenetics; overexpression; oxidant stress; patch clamp; pre-clinical; prevent; promoter; tau Proteins; tau aggregation; tau phosphorylation; trafficking; transmission process; two-photon

Summary Parkinson’s disease (PD) is the second most common neurodegenerative disease. Loss of substantia nigra compacta (SNc) dopaminergic projections and decreased striatal dopamine levels are the characteristic features of PD. Emerging evidence suggest that synaptic dysfunction of dopamine neurons is an early event in the pathogenesis of PD occurring prior to the onset of symptoms. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most prevalent causes of familial and sporadic PD, demonstrating an unprecedented significant role in PD pathogenesis. A transgenic mouse model with over-expression of human LRRK2- R1441G has been shown to recapitulate robust motor behavioral, neurochemical and pathological features of PD. At the level of pathology, the most robust phenotype is the axonopathy of the nigrostriatal dopaminergic projection, accompanied by age-dependent hyperphosphorylated tau and DA transmission deficits. Both genetic and environmental causes of PD have highlighted the importance of mitochondrial dysfunction in the pathogenesis of PD. Mitochondrial trafficking is critical for neurons’ survival and functions including synaptic neurotransmission. However, mitochondrial trafficking and dynamics in mutant LRRK2 associated-PD has not been well studied. We find that the mitochondrial oxidant stress is elevated in the LRRK2-R1441G mutants whereas mitochondrial respiration and mitochondrial ATP synthesis is significantly reduced. In addition, our preliminary studies uncovered early and defining features in mitochondria trafficking and dynamics impairment: frangmented mitochondria in SNc dopamine neurons and terminals, increased cytosolic calcum levels, tau hyperphosphorylation, and decreased anterograde healthy mitochondrial transport. We hypothesize that R1441G mutation impairs mitochondria trafficking and dynamics via dysregulation of Miro1 and calcium homeostasis and pathologic tau accumulation that ultimately result in synaptic dysfunction, energy failure and axonal degeneration. We will utilize a combination of two-photon imaging (2PLSM) and electrophysiology recording in living brain slices, and mouse genetics to uncover mechanisms underlying DAergic transmission deficits and axonal degeneration in PD.

总结 帕金森病（Parkinson's disease，PD）是第二常见的神经退行性疾病。损失 黑质多巴胺能投射和纹状体多巴胺减少 水平是PD的特征性特征。新出现的证据表明， 多巴胺神经元的功能障碍是PD发病机制中的早期事件， 症状的出现富含亮氨酸重复序列激酶2（LRRK 2）基因的突变是 家族性和散发性PD的最常见原因，显示出前所未有的显著性 在PD发病机制中的作用。过表达人LRRK 2基因的转基因小鼠模型的建立 R1441 G已被证明可以概括强大的运动行为，神经化学和 PD的病理特征。在病理学水平上，最强大的表型是 黑质纹状体多巴胺能投射轴突病，伴有年龄依赖性 过度磷酸化tau和DA传递缺陷。遗传和环境因素 近年来，线粒体功能障碍在PD发病机制中的重要性日益突出。 线粒体运输对于神经元的存活和功能，包括突触 神经传递然而，突变体LRRK 2的线粒体运输和动力学 相关PD尚未得到很好的研究。我们发现线粒体氧化应激是 在LRRK 2-R1441 G突变体中升高，而线粒体呼吸和线粒体呼吸抑制在LRRK 2-R1441 G突变体中升高。 ATP合成明显减少。此外，我们的初步研究发现， 线粒体运输和动力学损伤的定义特征：frangmented SNc多巴胺神经元和终末中的线粒体，细胞溶质钙水平升高，tau蛋白 过度磷酸化和减少的顺行健康线粒体转运。我们 假设R1441 G突变通过以下途径损害线粒体运输和动力学： Miro 1和钙稳态的失调以及病理性tau积累， 导致突触功能障碍、能量衰竭和轴突变性。我们将利用 活体脑双光子成像与电生理记录的结合 切片和小鼠遗传学，以揭示DA能传递缺陷的潜在机制 和轴突变性。