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

N-alpha-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 (alpha S) in the etiology of Parkinson's disease (PD) were performed using non-acetylated alpha S. The N-terminus of alpha-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-alpha-acetylation of alpha S a constitutive modification akin to most cellular proteins, or is it spatio-temporally regulated? Is N-alpha-acetylation of alpha S relevant to the as yet elusive function of alpha S? How does the N-alpha-acetylation of alpha S influence the aggregation of alpha S into amyloids? Here, we provide an overview of the current knowledge and discuss prevailing hypotheses on the impact of N-alpha-acetylation of alpha S on its conformational, oligomeric, and fibrillar states. The extent to which N-alpha-acetylation of alpha S is vital for its function, membrane binding, and aggregation into amyloids is also explored here. We further discuss the overall significance of N-alpha-acetylation of alpha S for its functional and pathogenic implications in Lewy body formation and synucleinopathies.

Automated summary

N-alpha-acetylation is a common post-translational modification in eukaryotic proteins, which has significant effects on protein regulation and function. However, the precise mechanisms and implications of N-alpha-acetylation of alpha-synuclein (alpha S) are not fully understood. This review provides an overview of current knowledge and discusses the impact of N-alpha-acetylation on the conformational, oligomeric, and fibrillar states of alpha S, as well as its relevance to Lewy body formation and synucleinopathies.