Alpha-Synuclein Toxicity: An Insight on Controversial Issues

α-Synuclein (α-syn) is a major constituent of neuronal inclusions known as Lewy bodies (LBs), which typically occur in Parkinson’s disease (PD) and “synucleinopathies.” Accumulation of α-syn aggregates occurs also in additional disorders, forming inclusions which may also feature aggregates of abnormal Tau protein. The hypothesis that accumulation of α-syn is key for neurodegeneration is grounded on familial forms of PD due to a specific mutation of α-syn or a duplication of the gene with abnormally high level of normally conformed α-syn. Thus, α-syn has been proposed to act as an endogenous neurotoxin. In this chapter, a detailed description of α-syn at synaptic level is provided. Then, the mechanisms and conditions through which α-syn might bear a detrimental role are extensively discussed, in particular, in neurological disorders and experimental models of neurodegeneration. In the last decades, several data have shown that overexpressed α-syn behaves as a neurotoxin through a variety of mechanisms; these include an impairment of cell-clearing system, a self-perpetuating fibrillization, a prion-like spreading from an area to another one, and also profiting of axonal transport. In particular, the mechanisms which regulate the clearance of α-syn such as the proteasome and autophagy, are discussed in relationship with an abnormal α-syn accumulation. In search not to cut any corner of such a complex issue, the beneficial effects of α-syn are described as well; among these is the neuroprotective effect to counteract methamphetamine-induced dopaminergic toxicity, which is bound to an antiapoptotic chaperone-like role.