LRRK2 G2019S promotes astrocytic inflammation induced by oligomeric -synuclein through NF-B pathway

Parkinson's disease (PD) is characterized by the irreversible loss of dopaminergic neurons and the accumulation of a-synuclein in Lewy bodies. The oligomeric alpha-synuclein (O-alpha S) is the most toxic form of alpha-synuclein species, and it has been reported to be a robust inflammatory mediator. Mutations in Leucine-Rich Repeat Kinase 2 (LRRK2) are also genetically linked to PD and neuroinflammation. However, how O-alpha S and LRRK2 interact in glial cells remains unclear. Here, we reported that LRRK2 G2019S mutation, which is one of the most frequent causes of familial PD, enhanced the effects of O-alpha S on astrocytes both in vivo and in vitro. Meanwhile, inhibition of LRRK2 kinase activity could relieve the inflammatory effects of both LRRK2 G2019S and O-alpha S. We also demonstrated that nuclear factor kappa B (NF-kappa B) pathway might be involved in the neuroinflammatory responses. These findings revealed that inhibition of LRRK2 kinase activity may be a viable strategy for suppressing neuroinflammation in PD.