Microglia: roles and genetic risk in Parkinson's disease

Abstract

The prevalence of neurodegenerative disorders such as Parkinson's disease are increasing as world populations age. Despite this growing public health concern, the precise molecular and cellular mechanisms that culminate in neurodegeneration remain unclear. Effective treatment options for Parkinson's disease and other neurodegenerative disorders remain very limited, due in part to this uncertain disease etiology. One commonality across neurodegenerative diseases is sustained neuroinflammation, mediated in large part by microglia, the innate immune cells of the brain. Initially thought to simply react to neuron-derived pathology, genetic and functional studies in recent years suggest that microglia play a more active role in the neurodegenerative process than previously appreciated. Here, we review evidence for the roles of microglia in Parkinson's disease pathogenesis and progression, with a particular focus on microglial functions that are perturbed by disease associated genes and mutations.

Keywords: Parkinson’s disease; genetic risk; microglia; neurodegeneration; neuroinflammation.

Figure 1

Key microglial functions in Parkinson’s disease. Microglia perform numerous homeostatic functions that support neuron health and counteract the development of disease. Characterized by high expression of markers such as P2RY12 and CX3CR1, they sense and remove a wide range of potentially detrimental substrates from the brain environment including various α-Synuclein species. Tunnelling nanotubes facilitate the direct intracellular transfer of α-Synuclein from neurons and healthy mitochondria to neurons. Trophic support and neuronal activity are other forms of support microglia provide to neurons. Microglia are also capable of harming neurons in multiple ways, including via neurotoxic cytokines, reactive oxygen species (ROS) and nitric oxide (NO), and by complement-mediated removal of synapses. In many cases, detrimental microglial effects are prompted by neuron-derived signals. α-Synuclein is prime among these, causing microglial inflammation and impairing homeostatic functions. Microglia in PD are often marked by high expression of genes such as IL1B, GPNMB and SPP1. Both genetic and environmental factors can impact neuron and/or microglial functions to promote neurodegeneration. Created with Biorender.com.