Subcellular localization of alpha-synuclein aggregates and their interaction with membranes

For more than a decade numerous evidence has been reported on the mechanisms of toxicity of alpha-synuclein (alpha S) oligomers and aggregates in alpha-synucleinopathies. These species were thought to form freely in the cytoplasm but recent reports of alpha S multimer conformations when bound to synaptic vesicles in physiological conditions, have raised the question about where alpha S aggregation initiates. In this review we focus on recent literature regarding the impact on membrane binding and subcellular localization of alpha S toxic species to understand how regular cellular function of alpha S contributes to pathology. Notably alpha S has been reported to mainly associate with specific membranes in neurons such as those of synaptic vesicles, ER/Golgi and the mitochondria, while toxic species of alpha S have been shown to inhibit, among others, neurotransmission, protein trafficking and mitochondrial function. Strategies interfering with alpha S membrane binding have shown to improve alpha S-driven toxicity in worms and in mice. Thus, a selective membrane binding that would result in a specific subcellular localization could be the key to understand how aggregation and pathology evolves, pointing out to alpha S functions that are primarily affected before onset of irreversible damage.