Figure 1. Microglial involvement in α-synucleinopathies (ASP).

Microglial cells can get activated by pathological α-synuclein (AS) (Su et al., 2009, Halliday and Stevens 2011, Fellner et al., 2013a). Different sources of these pathological AS species were proposed including release by neurons to the extracellular space or cell-to-cell propagation (Braak et al., 2007, Lee et al., 2010). Activation of microglial cells induces an oxidative stress response including the release of reactive oxygen species (ROS) and nitric oxide (NO) as well as the production of NADPH oxidase. Furthermore, pro-inflammatory cytokines, such as Interleukine-1β (IL-1β), IL-6, and tumor necrosis factor α (TNF-α), and the anti-inflammatory cytokine IL-10 as well as pro-inflammatory chemokines including (C-X-C motif) ligand 1 (CXCL-1), CXCL-10, Rantes, monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1α (MIP-1α) are released by activated microglial cells (Zhang et al., 2005, Su et al., 2008, Roodveldt et al., 2010, Alvarez-Erviti et al., 2011, Rojanathammanee et al., 2011, Fellner et al., 2013a). An involvement of Toll-like receptor 4 (TLR4), TLR2 and myeloperoxidase (MPO, key enzyme related to oxidative stress during inflammation) in inflammation and oxidative stress has been suggested (Stefanova et al., 2012a, Fellner et al., 2013a, Kim et al., 2013). Inflammation and oxidative stress mediated through microglial cells can further lead to neuronal dysfunction and cell death (Zhang et al., 2005, Reynolds et al., 2008). Thereby, dying neurons might release accumulated AS that stays in the extracellular space and again leads to the activation of microglial cells. This feedback loop might increase microglial activation leading to microgliosis. However, microglial cells are also able to phagocytose different forms of extracellular AS via TLR4 (Stefanova et al., 2011, Fellner et al., 2013a). This clearance mechanism might be even beneficial for neuronal survival. The different features displayed by microglial cells make it hard to categorize the role of microglial cells in ASP. Yet, the detrimental and beneficial functions of microglial cells suggest an involvement of microglial activation in the initiation and progression of ASP (Halliday and Stevens 2011). However, further studies have to be conducted to understand the complete participation of microglial activation in ASP.