BackgroundBrain injury has been suggested as a risk factor for neurodegenerative diseases. Accordingly, defects in the brain's intrinsic capacity to repair injury may result in the accumulation of damage and a progressive loss of brain function. The G2019S (GS) mutation in LRRK2 (leucine rich repeat kinase 2) is the most prevalent genetic alteration in Parkinson's disease (PD). Here, we sought to investigate how this LRRK2-GS mutation affects repair of the injured brain. MethodsBrain injury was induced by stereotaxic injection of ATP, a damage-associated molecular pattern (DAMP) component, into the striatum of wild-type (WT) and LRRK2-GS mice. Effects of the LRRK2-GS mutation on brain injury and the recovery from injury were examined by analyzing the molecular and cellular behavior of neurons, astrocytes, and monocytes. ResultsDamaged neurons express osteopontin (OPN), a factor associated with brain repair. Following ATP-induced damage, monocytes entered injured brains, phagocytosing damaged neurons and producing exosome-like vesicles (EVs) containing OPN through activation of the inflammasome and subsequent pyroptosis. Following EV production, neurons and astrocytes processes elongated towards injured cores. In LRRK2-GS mice, OPN expression and monocytic pyroptosis were decreased compared with that in WT mice, resulting in diminished release of OPN-containing EVs and attenuated elongation of neuron and astrocyte processes. In addition, exosomes prepared from injured LRRK2-GS brains induced neurite outgrowth less efficiently than those from injured WT brains. ConclusionsThe LRRK2-GS mutation delays repair of injured brains through reduced expression of OPN and diminished release of OPN-containing EVs from monocytes. These findings suggest that the LRRK2-GS mutation may promote the development of PD by delaying the repair of brain injury.