Microglial Phagocytosis and Its Regulation: A Therapeutic Target in Parkinson's Disease?

Abstract

The role of phagocytosis in the neuroprotective function of microglia has been appreciated for a long time, but only more recently a dysregulation of this process has been recognized in Parkinson's disease (PD). Indeed, microglia play several critical roles in central nervous system (CNS), such as clearance of dying neurons and pathogens as well as immunomodulation, and to fulfill these complex tasks they engage distinct phenotypes. Regulation of phenotypic plasticity and phagocytosis in microglia can be impaired by defects in molecular machinery regulating critical homeostatic mechanisms, including autophagy. Here, we briefly summarize current knowledge on molecular mechanisms of microglia phagocytosis, and the neuro-pathological role of microglia in PD. Then we focus more in detail on the possible functional role of microglial phagocytosis in the pathogenesis and progression of PD. Evidence in support of either a beneficial or deleterious role of phagocytosis in dopaminergic degeneration is reported. Altered expression of target-recognizing receptors and lysosomal receptor CD68, as well as the emerging determinant role of α-synuclein (α-SYN) in phagocytic function is discussed. We finally discuss the rationale to consider phagocytic processes as a therapeutic target to prevent or slow down dopaminergic degeneration.

Keywords: alpha-synuclein; cytokines; microglia; parkinson; phagocytosis.

Figure 1

Possible mechanisms of α-synuclein (α-SYN) oligomers phagocytosis in microglia. It is assumed that microglial phagocytosis is run by the same molecular machinery as in macrophages, partially overlapping with autophagy machinery. Proteins in red: documented evidence for an involvement in microglial phagocytosis, proteins in gray: possible role, not yet documented. Phagocytosis is initiated by the recognition of a cargo by specific phagocytosis receptors (TLRs, TREMs, TAMs or others). In case of α-SYN oligomers TLR2 and TLR4 are engaged. These receptors trigger at least three distinct molecular pathways leading to the production of: (1) lipidated-LC3 family proteins; (2) phospholipids (Phosphatidylinositol 3-phosphate, PI3P); and (3) second messengers (ROS), necessary for the delivery and fusion of phagosomes with lysosomes and degradation of the cargo. Lipidated-LC3 family proteins are produced by a cascade of events starting from unknown upstream events (likely mammalian target of rapamycin complex 1 (mTORC1) inhibition, not shown), leading to the activation of Atg3/Atg7 complex and Atg4 involved in the cleavage and lipidation of LC3 family precursors. BECN-1/Beclin-1 complex, in association with Rubicon is involved in PI3P production. ROS are produced by the activation of NOX complex, composed of PHOX subunits (p40, p47 and p67) and NOX2 and Rubicon. Beside activation of phagocytosis, TLR2/4 receptors lead to the activation to other biological responses, like indicated at the end of arrow 4. See text for details.