LRRK2 modulates phagocytic activity of microglia via phosphorylation of the actin-nucleating complex WAVE-2.

Time 2015-11-13 09:00~09:30 Place Room 605+606
Code No. BM-I09 Session Chair
Name Prof. David Park
Affiliation University of Ottawa
Title LRRK2 modulates phagocytic activity of microglia via phosphorylation of the actin-nucleating complex WAVE-2.
Contents
Mutations in leucine-rich repeat kinase 2 (LRRK2) are implicated in both familial and sporadic Parkinson’s disease (PD). Determining LRRK2’s function in the cell and subsequent role in dopaminergic cell death has been a challenge to elucidate. However, evidence in the field has been mounting that LRRK2 may play a robust role in immune cell function. Here we show both in vitro and in vivo that LRRK2 G2019S knock-in primary microglia and bone marrow-derived macrophages (BMDMs) display increased phagocytic activity that correlates with an increase in the ARP2/3 complex activator, WAVE-2. Conversely, LRRK2 null immune cells display impaired engulfment correlating with a decrease in WAVE-2 protein level. We also provide evidence that LRRK2 interacts and phosphorylates WAVE-2 at a serine residue to induce increased phagocytic activity. To explore LRRK2’s role only in microglia and its effect on neurons we expressed LRRK2 specifically in Drosophila CNS phagocytes (ensheathing cells) which leads to early death and age-dependant locomotor deficits. Taken together, our data may implicate microglial phagocytic hyper-activity in the pathogenesis of LRRK2-mediated Parkinson’s disease.