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.
Highlights
Microglia are brain professional phagocytes mainly finalized to clearance of apoptotic or necrotic cells (Green et al, 2016) and removal of unfolded proteins such as amyloid beta (Aβ) or neuromelanin
Phagocytosis of apoptotic neurons mediated by microglial triggering receptor expressed on myeloid cells-2 (TREM-2) was associated with decreased production of pro-inflammatory cytokines (Takahashi et al, 2005), while myelin debris phagocytosis enhanced the pro-inflammatory and dampened the anti-inflammatory profile in microglia (Siddiqui et al, 2016)
P.R47H variant of TREM-2 is associated with Parkinson’s disease (PD; Rayaprolu et al, 2013). This mini-review will focus on current understanding of the role of phagocytosis in PD, and how it is regulated at the physiological and molecular level and it will discuss whether phagocytotic activity might be considered a target for therapeutic intervention in PD
Summary
Microglia are brain professional phagocytes mainly finalized to clearance of apoptotic or necrotic cells (Green et al, 2016) and removal of unfolded proteins such as amyloid beta (Aβ) or neuromelanin. Microglia participate in remodeling of neuronal connectivity by engulfment of synapses, axonal and myelin debris (Paolicelli et al, 2011) and combat central infections by direct phagocytosis of bacteria and viruses (Nau et al, 2014). Phagocytosis is part of the innate immune response of microglia, and it mediates the adaptive responses by contributing to antigen presentation (Litman et al, 2005)
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