Ng Xin Yi, Cao Mian
Programme in Neuroscience and Behavioural Disorders, Duke-NUS Medical School, Singapore, Singapore.
Department of Physiology, National University of Singapore, Singapore, Singapore.
Neural Regen Res. 2024 Dec 1;19(12):2649-2660. doi: 10.4103/NRR.NRR-D-23-01624. Epub 2024 Mar 1.
Parkinson's disease is characterized by the selective degeneration of dopamine neurons in the nigrostriatal pathway and dopamine deficiency in the striatum. The precise reasons behind the specific degeneration of these dopamine neurons remain largely elusive. Genetic investigations have identified over 20 causative PARK genes and 90 genomic risk loci associated with both familial and sporadic Parkinson's disease. Notably, several of these genes are linked to the synaptic vesicle recycling process, particularly the clathrin-mediated endocytosis pathway. This suggests that impaired synaptic vesicle recycling might represent an early feature of Parkinson's disease, followed by axonal degeneration and the eventual loss of dopamine cell bodies in the midbrain via a "dying back" mechanism. Recently, several new animal and cellular models with Parkinson's disease-linked mutations affecting the endocytic pathway have been created and extensively characterized. These models faithfully recapitulate certain Parkinson's disease-like features at the animal, circuit, and cellular levels, and exhibit defects in synaptic membrane trafficking, further supporting the findings from human genetics and clinical studies. In this review, we will first summarize the cellular and molecular findings from the models of two Parkinson's disease-linked clathrin uncoating proteins: auxilin (DNAJC6/PARK19) and synaptojanin 1 (SYNJ1/PARK20). The mouse models carrying these two PARK gene mutations phenocopy each other with specific dopamine terminal pathology and display a potent synergistic effect. Subsequently, we will delve into the involvement of several clathrin-mediated endocytosis-related proteins (GAK, endophilin A1, SAC2/INPP5F, synaptotagmin-11), identified as Parkinson's disease risk factors through genome-wide association studies, in Parkinson's disease pathogenesis. We will also explore the direct or indirect roles of some common Parkinson's disease-linked proteins (alpha-synuclein (PARK1/4), Parkin (PARK2), and LRRK2 (PARK8)) in synaptic endocytic trafficking. Additionally, we will discuss the emerging novel functions of these endocytic proteins in downstream membrane traffic pathways, particularly autophagy. Given that synaptic dysfunction is considered as an early event in Parkinson's disease, a deeper understanding of the cellular mechanisms underlying synaptic vesicle endocytic trafficking may unveil novel targets for early diagnosis and the development of interventional therapies for Parkinson's disease. Future research should aim to elucidate why generalized synaptic endocytic dysfunction leads to the selective degeneration of nigrostriatal dopamine neurons in Parkinson's disease.
帕金森病的特征是黑质纹状体通路中多巴胺神经元的选择性退化以及纹状体中多巴胺缺乏。这些多巴胺神经元发生特异性退化的确切原因在很大程度上仍不清楚。基因研究已经确定了20多个与家族性和散发性帕金森病相关的致病PARK基因以及90个基因组风险位点。值得注意的是，其中几个基因与突触小泡循环过程有关，特别是网格蛋白介导的内吞途径。这表明突触小泡循环受损可能是帕金森病的早期特征，随后通过“逆向死亡”机制发生轴突退化以及中脑多巴胺细胞体的最终丧失。最近，已经创建并广泛表征了几种具有影响内吞途径的帕金森病相关突变的新动物和细胞模型。这些模型在动物、神经回路和细胞水平上忠实地重现了某些帕金森病样特征，并在突触膜运输方面表现出缺陷，进一步支持了来自人类遗传学和临床研究的结果。在这篇综述中，我们将首先总结两种与帕金森病相关的网格蛋白脱包被蛋白模型的细胞和分子研究结果：辅助蛋白（DNAJC6/PARK19）和突触素1（SYNJ1/PARK20）。携带这两种PARK基因突变的小鼠模型在特定的多巴胺终末病理方面相互模拟，并显示出强大的协同效应。随后，我们将深入探讨几种通过全基因组关联研究被确定为帕金森病风险因素的网格蛋白介导的内吞相关蛋白（GAK、内吞素A1、SAC2/INPP5F、突触结合蛋白-11）在帕金森病发病机制中的作用。我们还将探讨一些常见的与帕金森病相关的蛋白（α-突触核蛋白（PARK1/4）、帕金蛋白（PARK2）和富含亮氨酸重复激酶2（LRRK2，PARK8））在突触内吞运输中的直接或间接作用。此外，我们将讨论这些内吞蛋白在下游膜运输途径，特别是自噬中的新出现的功能。鉴于突触功能障碍被认为是帕金森病的早期事件，更深入地了解突触小泡内吞运输的细胞机制可能会揭示帕金森病早期诊断和干预治疗开发的新靶点。未来的研究应该旨在阐明为什么全身性突触内吞功能障碍会导致帕金森病中黑质纹状体多巴胺神经元的选择性退化。
