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

Sci Rep. 2017 Sep 12;7(1):11323. doi: 10.1038/s41598-017-11713-z.


Alpha synuclein (α-syn) is a central player in neurodegeneration, but the mechanisms triggering its pathology are not fully understood. Here we found that α-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 α-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 α-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 α-syn arginylation can be a previously unknown factor that facilitates normal α-syn folding and function in vivo.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Aminoacyltransferases / genetics
  • Aminoacyltransferases / metabolism
  • Animals
  • Arginine / metabolism*
  • Brain / physiology*
  • Cells, Cultured
  • Disease Models, Animal
  • Humans
  • Mass Spectrometry
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Neurodegenerative Diseases / metabolism*
  • Neurodegenerative Diseases / pathology
  • Neurodegenerative Diseases / prevention & control
  • Neurons / metabolism
  • Neurons / pathology
  • Peptides / chemistry
  • Peptides / metabolism
  • Protein Aggregates
  • Protein Aggregation, Pathological / metabolism
  • Protein Processing, Post-Translational
  • Proteolysis
  • Recombinant Proteins
  • Substrate Specificity
  • alpha-Synuclein / chemistry
  • alpha-Synuclein / metabolism*


  • Peptides
  • Protein Aggregates
  • Recombinant Proteins
  • alpha-Synuclein
  • Arginine
  • Aminoacyltransferases
  • Ate1 protein, mouse
  • arginyltransferase