AUTHOR=Iyer Aditya , Sidhu Arshdeep , Subramaniam Vinod 

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

JOURNAL=Frontiers in Neuroscience

VOLUME=16

YEAR=2022

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2022.1003997

DOI=10.3389/fnins.2022.1003997

ISSN=1662-453X

ABSTRACT=<p>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, <italic>in vitro</italic> 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 <italic>in vivo</italic>, however, there are many aspects of this post-translational modifications that are not understood well. Is <italic>N</italic>-α-acetylation of αS a constitutive modification akin to most cellular proteins, or is it spatio-temporally regulated? Is <italic>N</italic>-α-acetylation of αS relevant to the as yet elusive function of αS? How does the <italic>N</italic>-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 <italic>N</italic>-α-acetylation of αS on its conformational, oligomeric, and fibrillar states. The extent to which <italic>N</italic>-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 <italic>N</italic>-α-acetylation of αS for its functional and pathogenic implications in Lewy body formation and synucleinopathies.</p>