LRRK2 Inhibition Mitigates the Neuroinflammation Caused by TLR2-Specific α-Synuclein and Alleviates Neuroinflammation-Derived Dopaminergic Neuronal Loss

Evidence suggests that crosstalk occurs between microglial leucine-rich repeat kinase 2 (LRRK2)-a regulator of neuroinflammation-and neuron-released alpha -synuclein (alpha Syn)-a promoter of microglial activation and neuroinflammatory responses-in neuroinflammation-mediated Parkinson's disease (PD) progression. Therefore, we examined whether LRRK2 inhibition reduces the responses of microglia to neuroinflammation caused by neuron-released alpha Syn. We examined the neuroinflammatory responses provoked by Toll-like receptor 2 (TLR2)-positive alpha Syn of neuronal cells using an LRRK2 inhibitor in the mouse glioma cells, rat primary microglia, and human microglia cell line; and the effects of LRRK2 inhibitor in the co-culture of ectopic alpha Syn-expressing human neuroblastoma cells and human microglia cells and in mouse models by injecting alpha Syn. We analyzed the association between LRRK2 activity and alpha Syn oligomer and TLR2 levels in the substantia nigra tissues of human patients with idiopathic PD (iPD). The TLR2-specific alpha Syn elevated LRRK2 activity and neuroinflammation, and the LRRK2 inhibitor ameliorated neuroinflammatory responses in various microglia cells, alleviated neuronal degeneration along with neuroinflammation in the co-culture, and blocked the further progression of locomotor failure and dopaminergic neuronal degeneration caused by TLR2-specific alpha Syn in mice. Furthermore, LRRK2 phosphorylation was increased in patients with iPD showing alpha Syn-specific high TLR2 level. These results suggest the application of LRRK2 inhibitors as a novel therapeutic approach against alpha Syn-mediated PD progression.

Automated summary

Research suggests that LRRK2 inhibitors could be a novel therapeutic approach against alpha Syn-mediated Parkinson's disease progression. By inhibiting LRRK2 activity, the neuroinflammatory responses caused by neuron-released alpha Syn in microglia cells can be alleviated, thus slowing down the progression of PD.