LRRK2 Mutation Alters Dopamine D2 Receptor Localization in Induced Pluripotent Stem Cells-Derived Astrocytes From Parkinson's Disease Patients: Implications for Neuronal Damage

Astrocytes, the most abundant glia subtype, exert a wide range of functions, many of which are essential for maintaining neuronal homeostasis. A variety of neurotransmitter receptors are expressed on astrocytes allowing them to sense extracellular signals and respond by releasing neuroactive mediators. Among them, a wide variety of G protein-coupled receptors have been detected, including those for dopamine (DA), known to play a major role in modulating astrocytic activity. Evidence that astrocytic DA D2 receptors (D2R) increase the release of trophic factors and suppress neuroinflammation has been provided. Thus, DA signaling in astrocytes may be crucially involved in the mechanisms underlying the degeneration of DA neurons in Parkinson's disease (PD). In this study, human astrocytes were generated from induced pluripotent stem cell (iPSC) lines derived from two PD patients bearing G2019S LRRK2 kinase activating mutation. The effect of the PD-related mutation in astrocytes was analyzed, focusing on DA receptor's expression and localization. As expected, astrocytes carrying G2019S mutation in LRRK2 displayed a reactive phenotype with increased secretion of inflammatory cytokines and reduced ability to support DA neurons' trophism in astrocytes/neurons co-culture experiments. Intriguingly, PD astrocytes exhibited reduced membrane expression of D2R. Inhibiting the abnormally increased kinase activity was able to revert the PD astrocytes' reactive phenotype and to rescue the D2R membrane localization. We thus provide new insights into how G2019S mutation in LRRK2, by disrupting the astrocytic physiological localization of D2R, may impair protective DA signaling, resulting in increased neuroinflammation and neuronal damage. (Figure presented.).