Aquaporin-4 (AQP4) is essential for normal functioning of the brain’s glymphatic system. Impaired glymphatic function is associated with neuroinflammation. Recent clinical evidence suggests the involvement of glymphatic dysfunction in LRRK2-associated Parkinson’s disease (PD); however, the precise mechanism remains unclear. The pro-inflammatory cytokine interferon (IFN) γ interacts with LRRK2 to induce neuroinflammation. Therefore, we examined the AQP4-dependent glymphatic system’s role in IFNγ-mediated neuroinflammation in LRRK2-associated PD. We found that LRRK2 interacts with and phosphorylates AQP4 in vitro and in vivo. AQP4 phosphorylation by LRRK2 R1441G induced AQP4 depolarization and disrupted glymphatic IFNγ clearance. Exogeneous IFNγ significantly increased astrocyte expression of IFNγ receptor, amplified AQP4 depolarization, and exacerbated neuroinflammation in R1441G transgenic mice. Conversely, inhibiting LRRK2 restored AQP4 polarity, improved glymphatic function, and reduced IFNγ-mediated neuroinflammation and dopaminergic neurodegeneration. Our findings establish a link between LRRK2-mediated AQP4 phosphorylation and IFNγ-mediated neuroinflammation in LRRK2-associated PD, guiding the development of LRRK2 targeting therapy.

Aquaporin-4 (AQP4) 对于大脑类淋巴系统的正常功能至关重要。类淋巴功能受损与神经炎症有关。最近的临床证据表明， LRRK2相关的帕金森病 (PD)涉及类淋巴功能障碍；然而，确切的机制仍不清楚。促炎细胞因子干扰素 (IFN) γ 与 LRRK2 相互作用，诱导神经炎症。因此，我们研究了 AQP4 依赖性淋巴系统在LRRK2相关 PD 中 IFNγ 介导的神经炎症中的作用。我们发现 LRRK2 在体外和体内与 AQP4 相互作用并磷酸化 AQP4。LRRK2 R1441G引起的 AQP4 磷酸化诱导 AQP4 去极化并破坏类淋巴 IFNγ 清除。外源性 IFNγ 显着增加了R1441G转基因小鼠中星形胶质细胞 IFNγ 受体的表达，增强了 AQP4 去极化，并加剧了神经炎症。相反，抑制 LRRK2 可恢复 AQP4 极性，改善类淋巴功能，并减少 IFNγ 介导的神经炎症和多巴胺能神经变性。我们的研究结果建立了LRRK2相关 PD中 LRRK2 介导的 AQP4 磷酸化与 IFNγ 介导的神经炎症之间的联系，指导 LRRK2 靶向治疗的开发。