Relationship among α‑synuclein, aging and inflammation in Parkinson's disease (Review)

Abstract

Parkinson's disease (PD) is a common neurodegenerative pathology whose major clinical symptoms are movement disorders. The main pathological characteristics of PD are the selective death of dopaminergic (DA) neurons in the pars compacta of the substantia nigra and the presence of Lewy bodies containing α-synuclein (α-Syn) within these neurons. PD is associated with numerous risk factors, including environmental factors, genetic mutations and aging. In many cases, the complex interplay of numerous risk factors leads to the onset of PD. The mutated α-Syn gene, which expresses pathologicalα-Syn protein, can cause PD. Another important feature of PD is neuroinflammation, which is conducive to neuronal death. α-Syn is able to interact with certain cell types in the brain, including through phagocytosis and degradation of α-Syn by glial cells, activation of inflammatory pathways by α-Syn in glial cells, transmission of α-Syn between glial cells and neurons, and interactions between peripheral immune cells and α-Syn. In addition to the aforementioned risk factors, PD may also be associated with aging, as the prevalence of PD increases with advancing age. The aging process impairs the cellular clearance mechanism, which leads to chronic inflammation and the accumulation of intracellular α-Syn, which results in DA neuronal death. In the present review, the age-associated α-Syn pathogenicity and the interactions between α-Syn and certain types of cells within the brain are discussed to facilitate understanding of the mechanisms of PD pathogenesis, which may potentially provide insight for the future clinical treatment of PD.

Keywords: Parkinson's disease; aging; alpha-synuclein; astrocytes; dopaminergic neurons; microglia; neurodegenerative disorder; neuroinflammation; oligodendrocytes; peripheral immune cells.

Figure 1

α-Syn structure. The α-Syn protein contains (A) three distinct domains represented by different colors and (B) include seven highly conserved hexameric motifs, with the consensus for the hexameric motifs being-KTKEGV-. (C) Amino acid sequence of the α-Syn protein. A total of seven imperfect 11-amino-acid-residue repeats are underlined. The highly conserved hexameric motif in each repeat is indicated in red. The arrows and green highlighting indicate missense mutations. α-Syn, α-synuclein; NAC, non-A-β-amyloid component.

Figure 2

Possible mechanisms for intercellular transmission of α-Syn. α-Syn is released by neurons through TNTs and exosomes, as well as through a leaking process between pre- and post-synapses. α-Syn also spreads to nearby neuronal cells in a free-floating manner. Astrocytes engulf extracellular α-Syn and transfer it to other astrocytes through direct contact between cells, extracellular exosomes, vesicles and TNTs. The phagocytosis of extracellular α-Syn by astrocytes depends on TLR2, while the uptake of α-Syn by microglia is dependent on TLR2, TLR4, LAG3 and FcγRIIB. Microglia can also endocytose exosomes containing α-Syn and promote the transfer of α-Syn to neurons by releasing exosomal α-Syn. Hs is implicated in oligodendroglial uptake of extracellular α-Syn. α-Syn can be transferred from neurons to astrocytes, microglia and oligodendrocytes and can also be transferred from microglia to neurons, astrocytes to astrocytes and neurons to neurons. Astrocyte to neuron transfer is rare. α-Syn, α-synuclein; TNTs, tunneling nanotubes; TLR, Toll-like receptor; Hs, heparan sulfate; LAG3, lymphocyte-activation gene 3; FcγRIIB, Fc gamma receptor IIB.

Figure 3

Aging promotes the development of α-Syn pathology in the intestinal tract and α-Syn PFF transmission along the intestine-brain axis. The murine duodenal intestinal wall is inoculated with α-Syn PFFs and α-Syn is transferred to the brain through the vagus nerve, which causes α-Syn propagation between neurons. α-Syn pathology reduces the dopamine level in the striatum, resulting in movement dysfunction. Aged rats and mice are more likely to be vulnerable to α-Syn pathology in the intestinal tract compared with young rats and mice. Aging promotes α-Syn transmission along the intestine-brain axis. α-Syn, α-synuclein; PFFs, preformed fibrils.

Figure 4

Inflammatory activation of astrocytes and microglia by α-Syn and phenotypic switching between astrocytes and microglia. α-Syn induces the expression of CX3CL1, CCL5, IL-6 and TNF-α in astrocytes through the p38 MAPK and NF-κB signaling pathways. α-Syn aggregates also activate astrocytes and trigger neuroinflammation through the JNK and NF-κB signaling pathways. This leads astrocytes to express COX-2, iNOS, TNF-α and IL-1β. In microglia, α-Syn activates the MyD88-NF-κB signaling pathway, leading microglia to generate proinflammatory factors, including IL-6, IL-1β and TNF-α. α-Syn can prime and activate the microglial NLRP3 inflammasome, leading to the generation of IL-18 and IL-1β by microglia. Exosomal α-Syn suppresses autophagy in microglia through activation of the AKT/mTOR signaling pathway, which leads to accelerated extracellular α-Syn secretion and increased intracellular α-Syn accumulation. These inflammatory responses induced by α-Syn are conducive to DA neuronal death. α-Syn PFFs activate microglia into the M1 phenotype, which in turn induces astrocytes to develop into a neurotoxic A1 phenotype. The inflammatory responses in astrocytes are also capable of converting microglia into an M1-like phenotype. α-Syn, α-synuclein; PFFs, preformed fibrils; CX3CL1, C-X3-C motif chemokine ligand 1; CCL5, chemokine (C-C motif) ligand 5; COX-2, cyclooxygenase-2; iNOS, inducible nitric oxide synthase; NLRP3, nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing 3; MyD88, myeloid differentiation factor 88; DA, dopaminergic.

Figure 5

Adaptive immunity is implicated in PD pathogenesis. The inflammatory factors (IL-1β and TNF-α) produced by activated microglia act on microvascular endothelial cells, resulting in increased BBB permeability that facilitates NK cell, CD8⁺ T cell and CD4⁺ T cell entry into the brain. Likewise, astrocytes around the blood vessels produce inflammatory factors under pathological conditions, such as IL-6, IL-1β and TNF-α, which results in an increase in BBB permeability. Degradation of α-Syn may produce potentially antigenic peptides. Microglia and astrocytes express MHC-II proteins that present α-Syn antigenic peptides to CD4⁺ T cells, which are subsequently activated into proinflammatory Th17 and Th1 cells. α-Syn antigenic peptides can also be loaded onto MHC-I proteins and ultimately presented to CD8⁺ T cells by microglia. Th17 and Th1 cells are involved in enhancing inflammatory reactions, mediating PD pathology and inducing DA neuronal death. CD8⁺ T cells are involved in neuronal death and α-Syn aggregation in PD. PD, Parkinson's disease; BBB, blood-brain barrier; NK cells, natural killer cells; CD4, cluster of differentiation 4; CD8, cluster of differentiation 8; MHC-I, major histocompatibility complex class I; MHC-II, major histocompatibility complex class II; Th1 cells, type 1 T helper cells; Th17 cells, type 17 T helper cells; DA, dopaminergic.