How important is the N-terminal acetylation of alpha-synuclein for its function and aggregation into amyloids?

N-α-acetylation is a frequently occurring post-translational modification in eukaryotic proteins. It has manifold physiological consequences on the regulation and function of several proteins, with emerging studies suggesting that it is a global regulator of stress responses. For decades, in vitro biochemical investigations into the precise role of the intrinsically disordered protein alpha-synuclein (αS) in the etiology of Parkinson’s disease (PD) were performed using non-acetylated αS. The N-terminus of α-synuclein is now unequivocally known to be acetylated in vivo, however, there are many aspects of this post-translational modifications that are not understood well. Is N-α-acetylation of αS a constitutive modification akin to most cellular proteins, or is it spatio-temporally regulated? Is N-α-acetylation of αS relevant to the as yet elusive function of αS? How does the N-α-acetylation of αS influence the aggregation of αS into amyloids? Here, we provide an overview of the current knowledge and discuss prevailing hypotheses on the impact of N-α-acetylation of αS on its conformational, oligomeric, and fibrillar states. The extent to which N-α-acetylation of αS is vital for its function, membrane binding, and aggregation into amyloids is also explored here. We further discuss the overall significance of N-α-acetylation of αS for its functional and pathogenic implications in Lewy body formation and synucleinopathies.