Multiple evidences indicate that post-translational modifications (PTMs) of α-synuclein (α-Syn) play an important role in regulating the pathology of α-synucleinopathies, such as Parkinson’s disease (PD)1. In pathological Lewy bodies (LB), the most important component is phosphorylated α-Syn aggregates2,3. However, it is unclear how phosphorylation is related to α-Syn pathology.
Here, by combining chemical synthesis and protein expression, we obtained homogeneous α-Syn phosphorylated at specific sites (such as Tyr39, Ser129), which were found that these sites are phosphorylated in PD and are highly correlated with the pathological changes. The results showed that phosphorylation at Tyr39 (pY39) and Ser129 (pS129) induces α-Syn to form a distinct fibril with different structures and higher cytotoxicity compared with the wild-type α-Syn4,5,6. In addition, pTyr39 and pSer129 modulate the aggregation properties of α-Syn and induce α-Syn to form different stain4,5. Through cryo-electron microscopy (cryo-EM), we found that the entire N-terminus of pY39 α-Syn is involved into the fibril core, which may lead to the inability of molecular chaperones to mediate its clearance or protect α-Syn from protease digestion5. Therefore, the polymorphism of α-Syn stains may provide an explanation for high diversity of pathogenetic process. Furthermore, pS129 can enhance the interaction between α-Syn and receptors. The higher efficiency of pS129 α-Syn fibrils in cell internalization, seeding, and induction PD-like α-Syn pathology clarifies the spreading mechanism of phosphorylation on pathological α-Syn6.
These works illuminate the importance of PTMs in structure of amyloid aggregation and provide insight into the pathology of phosphorylated α-Syn in the progression of PD and α-synucleinopathies.