Interplay Between LRRK2 and Astrocytic DRD2 in the Context of Parkinson's Disease-Associated Neuroinflammation

Parkinson’s disease (PD) is a neurodegenerative disorder characterised by the selective loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc) in the midbrain. The prodromal phase represents the critical window for disease-modifying therapies, during which glial-mediated neuroinflammation plays a key role and astrocytes undergo reactive astrogliosis. Notably, dopamine exerts anti-inflammatory effects in striatal astrocytes by activating β-arrestin2 (β-arr2)-mediated Dopamine D2 Receptor (DRD2) signaling. β-arr2 acts as a “molecular brake” by inactivating Akt and blocking NLRP3 inflammasome assembly in the cytosol, preventing pro-inflammatory cytokine release. Gain-of-function mutations in LRRK2, encoding for a pleiotropic kinase, represent the leading genetic cause of familial PD. Our laboratory’s preliminary data demonstrated that astrocytes carrying the LRRK2-G2019S mutation exhibit a pro-inflammatory phenotype, impaired DRD2 signalling and trafficking. This study investigated whether LRRK2-dependent DRD2 inhibition exacerbates inflammation. At baseline, β-arr2 showed a significant increase in LRRK2-G2019S astrocytes compared to Wild-Type (WT), while GFAP levels remained unaltered. Moreover, upon inflammatory stimulation, both DRD2 genetic silencing and pharmacological inhibition reduced IL-1β secretion. Finally, establishing GFP-DRD2 overexpression enabled in situ mapping, showing DRD2-β-arr2 proximity without direct DRD2-NLRP3 interaction. Our findings highlight DRD2 overexpression as a valuable gain-of-function strategy to unravel astrocytic anti-inflammatory mechanisms and clarify β-arr2’s scaffolding function.