Protein arginylation targets alpha synuclein, facilitates normal brain health, and prevents neurodegeneration

Alpha synuclein (alpha-syn) is a central player in neurodegeneration, but the mechanisms triggering its pathology are not fully understood. Here we found that alpha-syn is a highly efficient substrate for arginyltransferase ATE1 and is arginylated in vivo by a novel mid-chain mechanism that targets the acidic side chains of E46 and E83. Lack of arginylation leads to increased alpha-syn aggregation and causes the formation of larger pathological aggregates in neurons, accompanied by impairments in its ability to be cleared via normal degradation pathways. In the mouse brain, lack of arginylation leads to an increase in alpha-syn's insoluble fraction, accompanied by behavioral changes characteristic for neurodegenerative pathology. Our data show that lack of arginylation in the brain leads to neurodegeneration, and suggests that alpha-syn arginylation can be a previously unknown factor that facilitates normal alpha-syn folding and function in vivo.