Synaptic Dysfunction and Energy Failure in Parkinson's Disease

摘要 帕金森病(PD)是第二常见的神经退行性疾病。损失 黑质致密区(SNC)多巴胺能投射与纹状体多巴胺减少 水平是帕金森病的特征。新出现的证据表明，突触 多巴胺神经元功能障碍是帕金森病发病机制中的早期事件 症状的出现。富含亮氨酸重复蛋白2(LRRK2)基因的突变是 家族性和散发性帕金森病的最常见原因，表现出前所未有的显著 在帕金森病发病中的作用。一种过表达人LRRK2的转基因小鼠模型 R1441G已被证明概括了强健的运动行为、神经化学和 帕金森病的病理特点。在病理水平上，最健壮的表型是 伴有年龄依赖性的黑质纹状体多巴胺能投射的轴索病变 过度磷酸化的tau和DA传递缺陷。既有遗传原因也有环境原因 线粒体功能障碍在帕金森病发病机制中的重要性。 线粒体运输对神经元的生存和包括突触在内的功能至关重要 神经传递。然而，突变体LRRK2的线粒体运输和动力学 关联性帕金森病一直没有得到很好的研究。我们发现线粒体氧化应激是 在LRRK2-R1441G突变体中升高，而线粒体呼吸和线粒体 ATP合成显著减少。此外，我们的初步研究发现，早期和 线粒体运输和动力学损伤的定义特征：错综复杂 黑质核多巴胺神经元和终末线粒体，胞浆钙水平升高，tau 过度磷酸化，并减少顺行健康的线粒体运输。我们 假设R1441G突变通过以下途径损害线粒体的运输和动力学 Miro1和钙稳态失调和病理性tau蓄积最终 导致突触功能障碍、能量衰竭和轴突变性。我们将利用一个 双光子成像(2PLSM)与电生理记录相结合的活脑研究 切片和小鼠遗传学以揭示DAR能传递缺陷的潜在机制 帕金森病患者轴突变性。

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.