Synaptic Dysfunction and Energy Failure in Parkinson's Disease

总结 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) 多巴胺能投射和纹状体多巴胺减少 水平是PD的特征。新出现的证据表明突触 多巴胺神经元功能障碍是 PD 发病机制中的一个早期事件，发生在 PD 之前。 症状出现。富含亮氨酸重复激酶 2 (LRRK2) 基因的突变是 家族性和散发性帕金森病最常见的病因，显示出前所未有的显着性 在 PD 发病机制中的作用。人类 LRRK2 过度表达的转基因小鼠模型 R1441G 已被证明能够重现强大的运动行为、神经化学和 PD的病理特征。在病理学水平上，最稳健的表型是 黑质纹状体多巴胺能投射的轴突病，伴有年龄依赖性 过度磷酸化的 tau 蛋白和 DA 传输缺陷。遗传和环境原因都有 PD 的研究强调了线粒体功能障碍在 PD 发病机制中的重要性。 线粒体运输对于神经元的生存和功能（包括突触）至关重要 神经传递。然而，突变体 LRRK2 中的线粒体运输和动力学 相关PD尚未得到充分研究。我们发现线粒体氧化应激是 LRRK2-R1441G 突变体中线粒体呼吸和线粒体呼吸作用升高 ATP 合成显着减少。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：支离破碎 SNc 多巴胺神经元和末梢中的线粒体、胞浆钙水平、tau 蛋白增加 过度磷酸化，并减少顺行健康线粒体运输。我们 假设 R1441G 突变通过以下方式损害线粒体运输和动力学 Miro1 和钙稳态的失调以及病理性 tau 积累最终导致 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) 和活体大脑电生理学记录的结合 切片和小鼠遗传学揭示 DAergic 传输缺陷的机制 和 PD 中的轴突变性。

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.