Alpha-Synuclein as a Prominent Actor in the Inflammatory Synaptopathy of Parkinson's Disease

Abstract

Parkinson's disease (PD) is considered the most common disorder of synucleinopathy, which is characterised by intracellular inclusions of aggregated and misfolded α-synuclein (α-syn) protein in various brain regions, and the loss of dopaminergic neurons. During the early prodromal phase of PD, synaptic alterations happen before cell death, which is linked to the synaptic accumulation of toxic α-syn specifically in the presynaptic terminals, affecting neurotransmitter release. The oligomers and protofibrils of α-syn are the most toxic species, and their overexpression impairs the distribution and activation of synaptic proteins, such as the SNARE complex, preventing neurotransmitter exocytosis and neuronal synaptic communication. In the last few years, the role of the immune system in PD has been increasingly considered. Microglial and astrocyte activation, the gene expression of proinflammatory factors, and the infiltration of immune cells from the periphery to the central nervous system (CNS) represent the main features of the inflammatory response. One of the actors of these processes is α-syn accumulation. In light of this, here, we provide a systematic review of PD-related α-syn and inflammation inter-players.

Keywords: dopamine; immune system; neuroinflammation; synaptopathy; α-synuclein.

Figure 1

The presynaptic exo-endocytotic cycle is specifically affected in α-syn-related synaptopaties. α-syn accumulation in the presynaptic terminals causes synaptopathy, ultimately leading to neurodegeneration. Under physiological conditions, α-syn, as a monomer, acts at the presynaptic terminals and activates a molecular machinery relevant to synaptic transmission, including the SNARE complex proteins, which recruit synaptic vesicles. After docking and priming, the vesicles undergo SNARE-mediated membrane fusion at the active zone, leading to neurotransmitter release into the synaptic cleft. Formation of toxic α-syn species in Parkinson’s disease (PD), such as oligomers and fibrils, has been shown to play a pivotal role in PD pathogenesis. These toxic species, which accumulate at the presynaptic terminal, lead to altered levels of proteins involved in synaptic transmission, determining synaptic dysfunction. Toxic α-syn accumulation affects the synapses, causing a lack of long-term synaptic plasticity expression, followed by an increase in the phosphorylation of glutamate receptors and a decrease in the GluN2A/GluN2B receptor subunit ratio, contributing to neuronal degeneration. Toxic aggregated α-syn forms participate in inflammatory processes mediated by microglia and astrocytes, which lose their normal physiological functions. Microglia become activated (M1) and trigger an immune response through increased receptor expression (MHCI), secretion of pro-inflammatory cytokines and chemokines, and inducing an astrocyte reaction (A1 type). Reactive astrocytes decrease glutamate uptake and release pro-inflammatory mediators. Finally, peripheral immune cells (T cells and monocytes) raid brain tissue and amplify neuroinflammation, contributing to neurodegeneration.