Figure 4. Mechanisms of α-synuclein aggregation and propagation.

Unfolded monomers of α-synuclein (α-syn) interact to form two types of dimers: anti-parallel dimers, which do not propagate, and parallel dimmers, which do propagate. A dynamic equilibrium is established between unfolded monomers and both forms of dimers. Interestingly, this process can take place either in the cytoplasm or in association with the cellular membrane. Propagating α-syn dimers can grow by the addition of unfolded monomers and generate ring-like oligomers and oligomers. Ring-like α-syn oligomers interact with the cytoplasmic membrane and form trans-membrane pores, inducing abnormal intracellular calcium influx. Cytoplasmic α-syn oligomers grow by the addition of soluble monomers, forming small amyloid fibrils and then longer fibrils. The accumulation of these amyloid fibrils leads to the formation of intracellular inclusions called Lewy bodies. During α-syn fibrillogenesis and aggregation, the intermediate species (oligomers and amyloid fibrils) are highly toxic, affecting mitochondrial function, endoplasmic reticulum (ER) – Golgi trafficking, protein degradation and/or synaptic transmission. These intracellular effects are thought to induce neurodegeneration. Interestingly, α-syn oligomers and fibrils, as well as the monomers, can be transferred between cells and induce disease spreading to other brain regions. Spreading mechanisms are multiple and can occur via endocytosis, direct penetration, transynaptic transmission, or via membrane receptors.