Leucine-rich repeat kinase-2 (LRRK2) modulates microglial phenotype and dopaminergic neurodegeneration

• DOI: 10.1016/j.neurobiolaging.2020.02.017
• Publication Date: 2020-02-27T01:28:54Z
• Authors: Zach Dwyer; Chris Rudyk; Ashley Thompson; Kyle Farmer; Barbara Fenner; Teresa Fortin; Alexa Derksen; Hongyu Sun; Shawn Hayley
• Keywords: LRRK2; Knockout mouse

Leucine-rich repeat kinase 2 (LRRK2) is a common gene implicated in Parkinson's disease and many inflammatory processes. Thus, we assessed the role of LRRK2 context endotoxin (lipopolysaccharide, LPS)-induced inflammation substantia nigra together with environmental toxicant, paraquat, that has been PD. Here found ablation prevented loss dopaminergic neurons behavioral deficits (motor) induced by LPS priming followed paraquat exposure. The also provoked phenotypic shift LPS-primed microglia cells. deficiency reduced their "activated" morphology upregulation phagocytic regulator, WAVE2 (critical for actin remodeling), while chemokine receptor, CX3CR1, was elevated isolated CD11b+ myeloid Furthermore, knockout attenuated signs oxidative stress morphological changes primary treatment. However, expression exposure overcame inhibitory effects knockout, suggesting may be acting downstream LRRK2. Neither nor did influence LPS-induced cytokine elevations microglia. We are first to show importance neurodegenerative processes this multi-hit toxin model These data consistent proposition useful therapeutic targets PD or other conditions prominent neuroinflammatory component.