N-Terminal Acetylation of α-Synuclein Slows down Its Aggregation Process and Alters the Morphology of the Resulting Aggregates

Abstract

Parkinson’s disease is associated with the aberrant aggregation of α-synuclein. Although the causes of this process are still unclear, post-translational modifications of α-synuclein are likely to play a modulatory role. Since α-synuclein is constitutively N-terminally acetylated, we investigated how this post-translational modification alters the aggregation behavior of this protein. By applying a three-pronged aggregation kinetics approach, we observed that N-terminal acetylation results in a reduced rate of lipid-induced aggregation and slows down both elongation and fibril-catalyzed aggregate proliferation. An analysis of the amyloid fibrils produced by the aggregation process revealed different morphologies for the acetylated and non-acetylated forms in both lipid-induced aggregation and seed-induced aggregation assays. In addition, we found that fibrils formed by acetylated α-synuclein exhibit a lower β-sheet content. These findings indicate that N-terminal acetylation of α-synuclein alters its lipid-dependent aggregation behavior, reduces its rate of in vitro aggregation, and affects the structural properties of its fibrillar aggregates.

The Strategies of Development of New Non-Toxic Inhibitors of Amyloid Formation

“…Fibrils formed from acetylated α-synuclein have a different morphology compared to the unmodified protein. Thus, a reduced amount of β-structure was found in their structure [ 75 ].…”

Effect of Modification Strategies on the Biological Activity of Peptides/Proteins

“…Although the protofibrils formed by N‐terminal acetylated proteins were morphologically similar to those formed by non‐acetylated α‐synuclein, their growth rate was slower. Moreover, Michele Vendruscolo's group [74] further investigated the effect of N‐terminal acetylation modification on the aggregation behavior of α‐synuclein using the thioflavin labeling method. The results are shown in Figure 5, where N‐terminal acetylation led to a decrease in the rate of lipid‐induced aggregation and slowed down the pro‐fibril‐catalyzed proliferation of aggregation at the same concentrations.…”

Synucleins: New Data on Misfolding, Aggregation and Role in Diseases

“…Various PTMs regulate α-synuclein susceptibility to aggregation by changing its conformation. PTMs such as phosphorylation, ubiquitination, acetylation, nitration, SUMOylation, etc., modify α-synuclein physicochemical properties and affect the aggregation process in synucleinopathies [ 11 , 12 , 29 , 31 , 32 , 33 , 34 ]. α-Synuclein is acetylated constitutively at its N-terminal ( Figure 1 ).…”

“…α-Synuclein is acetylated constitutively at its N-terminal ( Figure 1 ). As Bell et al recently demonstrated [ 11 , 12 ] this PTM changes the charge and spatial structure of α-synuclein and affects its aggregation and interaction with lipid membranes. Even subtle disturbances caused by PTMs as well as mutations, can lead to remarkable alterations in the aggregation performance of this protein [ 11 , 12 ].…”

“…Some missense mutations predisposing to diseases (A 53 E, A 53 T, A 30 P, E 46 K, H 50 Q, T 72 M, and E 83 Q) are displayed as blue letters above and under the α-synuclein image (Modified from [ 10 ]). At the upper left corner N-terminal acetylation of α-synuclein is shown, which slows down its aggregation and changes the morphology of the aggregates [ 11 , 12 ].…”