Role of α-synuclein in inducing innate and adaptive immunity in Parkinson disease

Abstract

Alpha-synuclein (α-syn) is central to the pathogenesis of Parkinson disease (PD). Gene duplications, triplications and point mutations in SNCA1, the gene encoding α-syn, cause autosomal dominant forms of PD. Aggregated and post-translationally modified forms of α-syn are present in Lewy bodies and Lewy neurites in both sporadic and familial PD, and recent work has emphasized the prion-like ability of aggregated α-syn to produce spreading pathology. Accumulation of abnormal forms of α-syn is a trigger for PD, but recent evidence suggests that much of the downstream neurodegeneration may result from inflammatory responses. Components of both the innate and adaptive immune systems are activated in PD, and influencing interactions between innate and adaptive immune components has been shown to modify the pathological process in animal models of PD. Understanding the relationship between α-syn and subsequent inflammation may reveal novel targets for neuroprotective interventions. In this review, we examine the role of α-syn and modified forms of this protein in the initiation of innate and adaptive immune responses.

Keywords: Parkinson disease; T-lymphocyte; adaptive immunity; alpha-synuclein; antigen presentation; innate immunity; microglia; post-translational modifications.

Figure 1. Model for α-synuclein-induced immune system activation in PD

α-Synuclein (α-syn) aggregates and other pathological conformations of α-syn form in the dopaminergic neurons of the substantia nigra during PD. Neighboring microglia take up this α-syn by either phagocytosis or fusion of α-syn-containing exosomes. Once inside the microglia, aggregated α-syn is targeted to the autophagolysosome, where it can be processed into peptides and loaded onto the MHC-II complex. The α-syn-loaded MHC-II traffics to the cell membrane, allowing for antigen presentation to CD4+ T-cells. Additionally, when α-syn enters the microglia, it induces NFκB-dependent expression of chemokines, which allows for migration of white blood cells, including T-cells, towards the site of injury. Once CD4+ T-cells enter the CNS, they are able to bind MHC-II via their T-cell receptor and thus, begin to release IFN-γ. IFN-γ then binds to its receptor on microglia, thereby inducing STAT-1-mediated pro-inflammatory cytokine expression. These cytokines then injure dopaminergic neurons and induce cell death. A similar process may occur in the enteric nervous system. Enteric neurons develop α-syn aggregates, and can release them to resident macrophages in one of three ways. First, α-syn is regularly phagocytosed by resident gut macrophages. Secondly, α-syn can be exocytosed, and finally, α-syn can be exosomally released. When primed M1-polarized macrophages take up aggregated α-syn, it is also targeted to the autophagolysosome, where it can be processed into peptides and loaded onto MHCII. In addition, α-syn then induces expression of both pro-inflammatory cytokines and chemokines. The CD4+ T-cell that binds to α-syn-loaded MHC-II will then activate and clonally expand. These T-cells would then be directing a body-wide specific immune response to α-syn and will respond quickly throughout the CNS as α-syn pathology spreads.