Division of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy.
Neurobiol Aging. 2021 Mar;99:65-78. doi: 10.1016/j.neurobiolaging.2020.12.001. Epub 2020 Dec 8.
Mutations in the leucine-rich repeat kinase 2 (LRRK2) are the most common genetic determinants of Parkinson's disease (PD), with the G2019S accounting for about 3% of PD cases. LRRK2 regulates various cellular processes, including vesicle trafficking that is crucial for receptor localization at the plasma membrane. In this study, induced pluripotent stem cells derived from 2 PD patients bearing the G2019S LRRK2 kinase activating mutation were used to generate neuronal cultures enriched in dopaminergic neurons. The results show that mutant LRRK2 prevents the membrane localization of both the dopamine D3 receptors (D3R) and the nicotinic acetylcholine receptors (nAChR) and the formation of the D3R-nAChR heteromer, a molecular unit crucial for promoting neuronal homeostasis and preserving dopaminergic neuron health. Interestingly, D3R and nAChR as well as the corresponding heteromer membrane localization were rescued by inhibiting the abnormally increased kinase activity. Thus, the altered membrane localization of the D3R-nAChR heteromer associated with mutation in LRRK2 might represent a pre-degenerative feature of dopaminergic neurons contributing to the special vulnerability of this neuronal population.
LRRK2 基因中的突变是帕金森病（PD）最常见的遗传决定因素，其中 G2019S 约占 PD 病例的 3%。LRRK2 调节多种细胞过程，包括囊泡运输，这对于受体在质膜上的定位至关重要。在这项研究中，使用来自携带 G2019S LRRK2 激酶激活突变的 2 名 PD 患者的诱导多能干细胞来生成富含多巴胺能神经元的神经元培养物。结果表明，突变型 LRRK2 阻止了多巴胺 D3 受体（D3R）和烟碱型乙酰胆碱受体（nAChR）的膜定位以及 D3R-nAChR 异源二聚体的形成，D3R-nAChR 异源二聚体是促进神经元内稳态和维持多巴胺能神经元健康的关键分子单元。有趣的是，通过抑制异常增加的激酶活性，挽救了 D3R 和 nAChR 以及相应的异源二聚体的膜定位。因此，与 LRRK2 突变相关的 D3R-nAChR 异源二聚体的异常膜定位可能代表多巴胺能神经元退行前的特征，导致该神经元群体的特殊易损性。
