LRRK2 contributes to monocyte dysregulation in Parkinson’s disease

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of familial Parkinson’s disease (PD) [20, 32]. Common polymorphisms in LRRK2 have been shown to modulate the risk for sporadic PD [6, 23, 24] strengthening the idea that inherited and sporadic PD share common underlying pathways. Although LRRK2 has been associated with a variety of cellular functions, including autophagy [1], mitochondrial function/dynamics [30] and microtubule/cytoskeletal dynamics [12], the overall physiological function of LRRK2 and its role in PD are only partially understood. Relatively recent studies also support a role for LRRK2 as regulator of inflammation. Substantial levels of LRRK2 protein and mRNA have been reported in immune cells like peripheral blood mononuclear cells (PBMCs), including B-cells, monocytes/macrophages, and dendritic cells [9, 13, 16, 29]. Moreover, LRRK2 has been shown to be involved in the activation and maturation of immune cells [29], in controlling the radical burst against pathogens in macrophages [9] and in modulating neuroinflammation by cytokine signaling [10, 19]. Remarkably, elevated levels of serum cytokines (IL-2, IL-4, IL-6, IL-10, TNFα) in PD patients [4, 22, 27] point to an involvement of the peripheral immune system in the pathogenesis of PD. Recently, we found an enrichment of “classical” CD14++CD16− monocyte subpopulation in the peripheral blood of PD patients together with a dysregulation of inflammatory pathways, phagocytosis deficits as well as hyperactivation of PD monocytes in response to LPS treatment, which correlated to PD severity [11]. Here, we sought to study the contribution of LRRK2 to the dysregulation of monocytes in Parkinson’s disease.