Astrocytic LRRK2 Controls Synaptic Connectivity through ERM Phosphorylation

Abstract

AbstractAstrocytes tightly control neuronal connectivity and function in the brain through direct contact with synapses1–5. These glial cells become reactive during disease pathogenesis6–8including Parkinson’s disease (PD)9–14. However, it remains unknown if astrocyte dysfunction is an initiating factor of PD pathogenesis and whether astrocytes can be targeted to stop or reverse the synaptic dysfunction seen in PD. Usingin vitroandin vivomethods, we found that the PD-linked gene Lrrk2 controls astrocyte morphology via regulating the phosphorylation of ERM proteins (Ezrin, Radixin, and Moesin), a structural component of the perisynaptic astrocyte processes. ERM phosphorylation is robustly elevated both in mice and humans carrying the LRRK2 G2019S Parkinsonism mutation. Importantly, the reduction of the ERM phosphorylation, specifically in the LRRK2 G2019S in adult astrocytes, is sufficient to restore excitatory synapse number and function deficits in the LRRK2 G2019S knock-in mouse cortex. These results show a role for Lrrk2 in controlling astrocyte morphogenesis and synaptogenic function and reveal that early astrocyte dysfunction in PD could be causal to disruptions in cortical excitatory synaptic connectivity. The astrocytic dysfunction can be corrected by dampening ERM phosphorylation, pinpointing astrocytes as critical cellular targets for PD therapeutics.