Abstract:
Background: Parkinson\'s disease (PD) is marked by the loss of dopaminergic neurons in the substantia nigra pars compacta, leading to motor and cognitive dysfunctions. The molecular mechanisms underlying synaptic alterations in PD remain elusive, with a focus on the role of Itga5 in synaptic integrity and motor coordination and TAT-Itga5 was designed to suppress PTEN activity in this investigation. Methods: This study utilized MPTP-induced PD animal models to investigate the expression and role of Itga5 in the striatum. Techniques included quantitative PCR, Western blotting, immunostaining, CRISPR-CasRx-mediated knockdown, electrophysiological assays, behavioral tests, and mass spectrometry. Results: Itga5 expression was significantly reduced in MPTP-induced PD models. In these models, a marked decrease in dendritic spine density and a shift towards thinner spines in striatal GABA neurons were observed, suggesting impaired synaptic integration. Knockdown of Itga5 resulted in reduced dendritic branching, decreased mushroom spines, and increased thin spines, altering synaptic architecture. Electrophysiological analyses revealed changes in action potential and spontaneous excitatory postsynaptic currents, indicating altered synaptic transmission. Motor behavior assessments showed that Itga5 deficiency led to impairments in fine motor control and coordination. Furthermore, Itga5 was found to interact with PTEN, affecting AKT signaling crucial for synaptic development and motor coordination. Conclusion: The study demonstrates that Itga5 plays a critical role in maintaining synaptic integrity and motor coordination in PD. The Itga5-PTEN-AKT pathway represents a potential therapeutic target for addressing synaptic and motor dysfunctions in PD.
摘要:
背景:帕金森病(PD)的特征是黑质致密质中多巴胺能神经元的丢失,导致运动和认知功能障碍。PD突触改变的分子机制仍然难以捉摸,在这项研究中,重点研究了Itga5在突触完整性和运动协调中的作用,并且设计了TAT-Itga5来抑制PTEN活性。方法:本研究利用MPTP诱导的PD动物模型研究Itga5在纹状体中的表达和作用。技术包括定量PCR,西方印迹,免疫染色,CRISPR-CasRx介导的敲减,电生理学测定,行为测试,和质谱。结果:在MPTP诱导的PD模型中,Itga5表达显著降低。在这些模型中,观察到纹状体GABA神经元的树突棘密度显着降低,并且向更细的棘转移,提示突触整合受损。击倒Itga5导致树突状分支减少,减少蘑菇刺,增加了细刺,改变突触结构。电生理分析显示动作电位和自发兴奋性突触后电流的变化,表明突触传递改变。运动行为评估表明,Itga5缺乏导致精细运动控制和协调能力受损。此外,发现Itga5与PTEN相互作用,影响对突触发育和运动协调至关重要的AKT信号传导。结论:研究表明,Itga5在维持PD的突触完整性和运动协调中起着至关重要的作用。Itga5-PTEN-AKT途径代表了解决PD中突触和运动功能障碍的潜在治疗靶标。