Chen Chuyu, He Qianzi, Tombesi Giulia, Napier Eve, Jaconelli Matthew, Moreno-Ramos Oscar Andrés, Serio Hannah, Naaldijk Yahaira, Promes Vanessa, Schneeweis Amanda, Quinn Kaitlyn, Nasios Christopher, Greggio Elisa, Kozorovitskiy Yevgenia, Arango Daniel, Khan Amir R, Alessi Dario R, Dombeck Daniel A, Hilfiker Sabine, Awatramani Rajeshwar, Parisiadou Loukia
Department of Pharmacology, Northwestern University, Chicago, IL, USA.
Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
bioRxiv. 2025 Sep 3:2025.08.28.672006. doi: 10.1101/2025.08.28.672006.
The end-stage pathology of Parkinson's disease (PD) involves the loss of dopamine-producing neurons in the substantia nigra pars compacta (SNc). However, synaptic deregulation of these neurons begins much earlier. Understanding the mechanisms behind synaptic deficits is crucial for early therapeutic intervention, yet these remain largely unknown. In the SNc, different dopamine neuron subtypes show varying susceptibility patterns to PD, complicating our understanding. This study uses intersectional genetic mouse models to uncover synaptic perturbations in vulnerable dopamine neurons, focusing on the LRRK2 kinase, a protein closely linked to PD. Through a combination of immunofluorescence and advanced proximity labeling methods, we found higher LRRK2 expression in the most vulnerable dopamine neuron subclusters. High-resolution imaging revealed that pathogenic LRRK2 disrupts release sites in vulnerable dopamine axons, leading to decreased in vivo evoked striatal dopamine release in mice with LRRK2 mutations. Proteomic and biochemical analyses indicate that mutant LRRK2 increases the phosphorylation of RAB3 proteins, reducing their interactions with RIM1/2 effector proteins and impacting their synaptic functions. Overall, this research highlights the cell-autonomous dysfunctions caused by mutant LRRK2 in the neurons that are primarily affected by the disease. It also provides a framework for therapeutic strategies for early nigrostriatal synaptic deficits in PD.
帕金森病（PD）的终末期病理表现为黑质致密部（SNc）中产生多巴胺的神经元缺失。然而，这些神经元的突触失调在更早阶段就已开始。了解突触缺陷背后的机制对于早期治疗干预至关重要，但这些机制在很大程度上仍不清楚。在SNc中，不同的多巴胺神经元亚型对PD表现出不同的易感性模式，这使我们的理解变得复杂。本研究使用交叉遗传小鼠模型来揭示易损多巴胺神经元中的突触扰动，重点关注与PD密切相关的LRRK2激酶。通过免疫荧光和先进的邻近标记方法相结合，我们发现在最易损的多巴胺神经元亚群中LRRK2表达更高。高分辨率成像显示，致病性LRRK2破坏了易损多巴胺轴突中的释放位点，导致携带LRRK2突变的小鼠体内诱发的纹状体多巴胺释放减少。蛋白质组学和生化分析表明，突变型LRRK2增加了RAB3蛋白的磷酸化，减少了它们与RIM1/2效应蛋白的相互作用，并影响了它们的突触功能。总体而言，这项研究突出了突变型LRRK2在主要受该疾病影响的神经元中引起的细胞自主功能障碍。它还为PD早期黑质纹状体突触缺陷的治疗策略提供了一个框架。
