Parkinson's disease-linked leucine-rich repeat kinase 2(R1441G) mutation increases proinflammatory cytokine release from activated primary microglial cells and resultant neurotoxicity

Mutations in leucine-rich repeat kinase 2 (LRRK2) have been causally linked to neuronal cell death in Parkinson's disease. LRRK2 expression has also been detected in B lymphocytes and macrophages, suggesting a role in immune responses. In the present study, we demonstrate that LRRK2 is expressed in primary microglial cells isolated from brains of adult mice. Moreover, lipopolysaccharide (LPS)-activated microglial cells from mice overexpressing the Parkinson's disease-linked LRRK2(R1441G) mutation exhibit increased expression and secretion of proinflammatory cytokines compared with wild-type control microglia. Expression of the LPS receptor Toll-like receptor 4 (TLR4) and downstream signaling proteins did not differ between LRRK2(R1441G) transgenic microglia and wild-type controls. Consistently, conditioned medium from LPS-stimulated LRRK2(R1441G) transgenic microglia induced significant cell death when added to neuronal cultures. These findings indicate that enhanced neuroinflammation may contribute to neurodegeneration in Parkinson's disease patients carrying LRRK2 mutations.

▶LRRK2 protein is expressed in microglial cells isolated from brains of adult mice. ▶Activated LRRK2(R1441G) microglia secretes higher amounts proinflammatory cytokines. ▶Conditioned medium from activated LRRK2(R1441G) microglia causes neuronal cell death. ▶Mutant LRRK2 acts upstream of cytokine gene induction.