The Contribution of α-Synuclein Spreading to Parkinson’s Disease Synaptopathy

Monomeric, oligomeric, and fibrillary α-synuclein at the synaptic terminal. (a) Monomeric α-synuclein modulates synaptic function by controlling synaptic vesicle release. This form of the protein can be released in association with exosomes, activates microglial cells, and can be internalized at postsynaptic sites. (b) Oligomeric α-synuclein formation is enhanced by interaction of monomeric protein with DA. Alpha-synuclein oligomers can form a stable adduct with the toxic dopamine metabolite DOPAL. Oligomers can be released in association with extracellular vesicles and then activate microglia. Alpha-synuclein oligomers can disrupt synaptic vesicles membranes as well as presynaptic and postsynaptic membranes. Exogenous α-synuclein oligomers can damage lipid rafts and affect LTP by activating NMDA receptors. Intracellular α-synuclein oligomers with endogenous or exogenous origin impair mitochondrial functions and cytoskeletal architecture. (c) Fibrillary-aggregated α-synuclein alters synaptic vesicle release by clustering synaptic vesicles and by perforating plasma membrane. Extracellular fibrils deriving from degenerating neurons in the PD brain can activate microglial cells and actively contribute to alpha-synuclein pathology spreading. The formation of endogenous α-synuclein fibrils can reduce seeding activity and toxicity although exogenous α-synuclein fibrils function as a seed for the aggregation of endogenous α-synuclein in recipient cells.