Intracellular Alpha-Synuclein and Immune Cell Function

Abstract

Intracellular alpha-synuclein has numerous effects on different functions of the cell. Although it is expressed in a wide spectrum of cell types from different lineages, most of our knowledge about it was generated by studying neuronal or glial cells. However, the role of immune cells in Parkinson's disease and related synucleinopathies has recently emerged. Altered immune cell phenotypes and functions have been reported not only in animal models, but also in human disease. While the response of immune cells to extracellular alpha-synuclein has been thoroughly studied, insights into the effects of endogenously expressed or taken-up alpha-synuclein on the function of immune cells remain scarce. Such insights may prove to be important for understanding the complex cellular and molecular events resulting in neurodegeneration and aid the development of novel therapies. We review the current state of knowledge about how alpha-synuclein and its pathologic manifestations affect the phenotype and function of peripheral and central nervous system (CNS) immune cells, and discuss the potential of this topic for advancing our understanding of synucleinopathies.

Keywords: Parkinson’s disease; alpha-synuclein; immune cell function; microglia; monocytes.

FIGURE 1

Alpha-synuclein and immune cell function. Different mechanisms can contribute to the pool of intracellular α-synuclein (black arrows). Alpha-synuclein is weakly expressed in immune cells, most notably microglia, macrophages and inflammatory monocytes (panel sizes correspond to estimated relative expression). Extracellular alpha-synuclein can also contribute to the intracellular pool after uptake. Extracellular alpha-synuclein can induce the immune response by binding to molecular pattern receptors on the cell surface or the lumen of endocytic vesicles (red). Different putative mechanisms can contribute to the effects of intracellular alpha-synuclein on immune cell function (blue arrows). NK, natural killer cells; ROS, reactive oxygen species; SNCA, alpha-synuclein gene.