帕金森病异动症发生中 ALDH1A1介导的MOR通路参与纹状体功能调控的研究

L-3, 4-Dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) is a major clinical complication in the treatment of Parkinson’s disease (PD). Our preliminary studies showed that expression of enkephalin (ENK) was increased in Parkinson’s disease patients displaying treatment-related dyskinesia than age-matched non-parkinsonian control. The study showed that the expression of receptor micron opioid receptor (MOR) was regulated by many factors. Our project proposes the MOR signaling pathway to participate in the LID. . Our preliminary findings demonstrate that ALDH1A1–synthesized RA is required for maintaining postsynaptic MOR signaling. Based on those, we designed AAV-Aldh1a1 shRNA，AAV-EF1a-Flex-Aldh1a1and used RA to treat LID model. We detect the protein interaction, protein activation and regulation of MOR signaling pathway in LID of 6-OHDA unilateral lesion rat and dopamine–depleted Pitx3 (upstream of ALDH1A1) null mice. We explore the role of downstream ERK signaling pathway in LID thereby regulating the abnormal activation of the MOR pathway, eventually revealing LID. ALDH1A1 mediated MOR expression in LID maybe is an important molecular mechanism, which provides theoretical and experimental basis for to explore a new approach to LID therapy.

左旋多巴诱导的异动症(LID)是帕金森病(PD)主要的并发症。我们前期实验表明脑啡肽(ENK)在PD合并LID患者死后脑片中表达增多，研究显示其受体－μ阿片受体(MOR)的表达受多种因素调控。本项目提出MOR信号通路参与LID假说。我们早期结果显示乙醛脱氢酶(ALDH1A1)能够合成视黄酸(RA)并调控纹状体突触后MOR表达。依据成熟技术，设计针对ALDH1A1的病毒以及使用RA，借助经典6-OHDA单侧损毁大鼠以及多巴胺缺乏Pitx3(ALDH1A1上游)敲除小鼠L-DOPA处理后LID模型，检测MOR信号通路蛋白相互作用、活化以及对这种作用的调节，期望干扰LID中ALDH1A1的表达，从而调节MOR通路的异常表达，继而抑制下游ERK信号通路异常活化，最终减轻LID行为。从而揭示PD中ALDH1A1介导的MOR表达是导致LID一重要分子机制，为探索LID治疗的新途径提供理论及实验依据。

左旋多巴诱导的异动症(LID)是帕金森病(PD)主要的并发症。乙醛脱氢酶1A1（ALDH1A1）是一种视黄酸（RA）合成酶，由帕金森病（PD）中优先退化的黑质纹状体多巴胺能（nDA）神经元。ALDH1A1阳性轴突主要投射到背侧纹状体。然而，ALDH1A1及其调节突触后纹状体神经元活动的产物尚不清楚。这里我们揭示了背侧纹状体中μ型阿片受体（MOR1）水平严重降低Aldh1a1敲除小鼠，RA能够挽救这种减少的表达。此外RA治疗还上调纹状体MOR1水平和信号传导，并减轻L-DOPA诱导的Pitx3敲除小鼠（缺乏ALDH1A1表达的缺陷小鼠nDA神经元）LID模型。ALDH1A1合成的RA对于背侧纹状体的突触后MOR1表达， RA对调节L-DOPA诱导的运动障碍有明确的治疗作用，继而抑制下游ERK信号通路异常活化，最终减轻LID行为。从而揭示PD中ALDH1A1介导的MOR1表达是导致LID一重要分子机制，为探索LID治疗的新途径提供理论及实验依据。