Mechanisms of alpha-synuclein toxicity: An update and outlook

Alpha-synuclein (aSyn) was identified as the main component of inclusions that define synucleinopathies more than 20 years ago. Since then, aSyn has been extensively studied in an attempt to unravel its roles in both physiology and pathology. Today, studying the mechanisms of aSyn toxicity remains in the limelight, leading to the identification of novel pathways involved in pathogenesis. In this chapter, we address the molecular mechanisms involved in synucleinopathies, from aSyn misfolding and aggregation to the various cellular effects and pathologies associated. In particular, we review our current understanding of the mechanisms involved in the spreading of aSyn between different cells, from the periphery to the brain, and back. Finally, we also review recent studies on the contribution of inflammation and the gut microbiota to pathology in synucleinopathies. Despite significant advances in our understanding of the molecular mechanisms involved, we still lack an integrated understanding of the pathways leading to neurodegeneration in PD and other synucleinopathies, compromising our ability to develop novel therapeutic strategies.