Neuroinflammation is a prominent feature of Parkinson's disease (PD) and can contribute to disease progression through loss of dopaminergic (DA) neurons in the substantia nigra (SN) of the brain. Elevated levels of pro-inflammatory cytokines and extensive proliferation of reactive microglia around dopaminergic neurons have been detected in the SN of post-mortem brains from PD patients (1). Notably, microglia are enriched in SN compared to other regions of the brain. These findings, coupled to reduced antioxidant capacity and enhanced sensitivity of neurons to pro-inflammatory molecules, support a role for microglia-mediated DA degeneration in PD.
The leucine-rich repeat kinase 2 (LRRK2) protein may act as a mediator of inflammation through cytokine signaling and microglia-mediated pro-inflammatory responses. Mutations in the LRRK2 gene are the most common cause of familial PD. LRRK2 is a multi-functional protein with ubiquitous expression; its mRNA and protein levels are highly expressed in immune and glial cells, and neurons (1). Recent findings indicate the presence of LRRK2 splice variants in the brain with neurons and astrocytes expressing a different variant than microglia, suggesting a differential function for this protein in various cell types (2). In line with these observations, lipopolysaccharide (LPS)-induced inflammation in mice was associated with upregulation of LRRK2 protein expression and activity in microglia (3). Furthermore, down-regulation of microglial LRRK2 protein expression attenuated LPS-induced inflammatory responses through pro-inflammatory cytokine signaling. Interestingly, gene expression profiling of microglia from mice that over-express LRRK2 R1441G, a disease-associated mutation, revealed an expression profile corresponding to reactive and pro-inflammatory phenotype under normal, unstimulated conditions (1). These combined findings indicate a role for LRRK2 in cellular pathways that induce inflammation and that its dysfunction may exacerbate microglial pro-inflammatory responses that would ultimately lead to neurodegeneration.
1. Russo I, et al. 2014. J. Neuroinflammation. 11:52. Pubmed
2. Giesert F, et al. 2013. PLoS One. 8(5): e63778. Pubmed
3. Moehle MS, et al. 2012. J. Neurosci. 32(5):1602. Pubmed