N-terminal acetylation reduces synuclein pathology in models of Parkinson's disease.

α-synuclein protein is a major constituent of pathological intracellular inclusions such as Lewy bodies found in brains of patients with Parkinson's disease and other synucleinopathies. Whereas α-synuclein phosphorylation has been much studied, comparatively less work has been devoted to other post-translational modifications such as acetylation, especially given that N-terminally acetylated α-synuclein is the most abundant endogenous form of the protein in the brain. In this study, using multiple in vitro and in vivo models of Parkinson's disease, we sought to understand the pathological consequences of N-terminally acetylated α-synuclein. We found that N-terminal acetylation slowed aggregation of both α-synuclein monomers and pre-formed fibrils in seed amplification assay. Uptake of acetylated pre-formed fibrils into both immortalized cell lines and iPSC-derived dopamine neurons was slowed compared to non-acetylated fibrils. In addition, exposure to acetylated pre-formed fibrils induced less seeding of endogenous α-synuclein, as measured by the accumulation of serine129-phosphorylated α-synuclein inclusions in both iPSC-derived dopamine neurons and mice brains. Finally, mice injected with N-terminally acetylated α-synuclein pre-formed fibrils survived significantly longer than mice injected with non-acetylated fibrils. Taken together, our study indicates that N-terminal acetylation reduces α-synuclein aggregation, uptake into cells, seeding of endogenous α-synuclein, and toxicity in vivo, suggesting that this prevalent post-translational modification represents a potent, physiologically relevant protective mechanism, which has thus far largely not been taken into consideration in most experimental paradigms of Parkinson's disease and synucleinopathies.