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

Parkinson's disease (PD) is considered the most common disorder of synucleinopathy, which is characterised by intracellular inclusions of aggregated and misfolded alpha-synuclein (alpha-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 alpha-syn specifically in the presynaptic terminals, affecting neurotransmitter release. The oligomers and protofibrils of alpha-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 alpha-syn accumulation. In light of this, here, we provide a systematic review of PD-related alpha-syn and inflammation inter-players.

Automated summary

Parkinson's disease is characterized by the aggregation of alpha-synuclein protein in brain regions and the loss of dopaminergic neurons, which leads to synaptic alterations and immune system activation. Toxic species of alpha-syn, such as oligomers and protofibrils, impair synaptic protein distribution and neurotransmitter release, while inflammatory response mediated by microglia and astrocytes is linked to alpha-syn accumulation in the central nervous system.