编码富含亮氨酸的重复序列激酶2(LRRK2)的LRRK2的基因突变,与帕金森病(PD)最常见的单基因形式之一有关。然而,Gly2019Ser(G2019S)突变的潜在效应子仍然未知.在这项研究中,作者研究了LRRK2G2019S对诱导多能干细胞(iPSC)诱导的多巴胺神经元内质网(ER)应激的影响,并探索了小鼠模型的潜在治疗靶点。这些发现表明LRRK2G2019S显著促进神经元和小鼠的ER应激。有趣的是,抑制LRRK2活性可以改善突变引起的内质网应激。此外,LRRK2突变可通过与血小板反应蛋白-1/转化生长因子β1(THBS1/TGF-β1)直接相互作用来诱导内质网应激。抑制LRRK2激酶活性可有效抑制内质网应激和THBS1/TGF-β1的表达。敲除THBS1可以通过与TGF-β1和LRRK2突变引起的行为负担相互作用来挽救ER应激,而抑制TGF-β1具有类似的效果。总的来说,已证明LRRK2突变通过直接与THBS1/TGF-β1相互作用来促进ER应激,从而导致PD中的神经死亡。这些发现为PD的发病机理提供了有价值的见解,突出潜在的诊断标志物和治疗靶点。
The gene mutations of LRRK2, which encodes leucine-rich repeat kinase 2 (LRRK2), are associated with one of the most prevalent monogenic forms of Parkinson\'s disease (PD). However, the potential effectors of the Gly2019Ser (G2019S) mutation remain unknown. In this study, the authors investigate the effects of LRRK2 G2019S on endoplasmic reticulum (ER) stress in induced pluripotent stem cell (iPSC)-induced dopamine neurons and explore potential therapeutic targets in mice model. These findings demonstrate that LRRK2 G2019S significantly promotes ER stress in neurons and mice. Interestingly, inhibiting LRRK2 activity can ameliorate ER stress induced by the mutation. Moreover, LRRK2 mutation can induce ER stress by directly interacting with thrombospondin-1/transforming growth factor beta1 (THBS1/TGF-β1). Inhibition of LRRK2 kinase activity can effectively suppress ER stress and the expression of THBS1/TGF-β1. Knocking down THBS1 can rescue ER stress by interacting with TGF-β1 and behavior burden caused by the LRRK2 mutation, while suppression of TGF-β1 has a similar effect. Overall, it is demonstrated that the LRRK2 mutation promotes ER stress by directly interacting with THBS1/TGF-β1, leading to neural death in PD. These findings provide valuable insights into the pathogenesis of PD, highlighting potential diagnostic markers and therapeutic targets.