LRRK2 Gly2019Ser Mutation Promotes ER Stress via Interacting with THBS1/TGF‐β1 in Parkinson's Disease

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.