Extracellular vesicle sorting of α-Synuclein is regulated by sumoylation

Acta Neuropathol. 2015 May;129(5):695-713. doi: 10.1007/s00401-015-1408-1. Epub 2015 Mar 17.


Extracellular α-Synuclein has been implicated in interneuronal propagation of disease pathology in Parkinson's Disease. How α-Synuclein is released into the extracellular space is still unclear. Here, we show that α-Synuclein is present in extracellular vesicles in the central nervous system. We find that sorting of α-Synuclein in extracellular vesicles is regulated by sumoylation and that sumoylation acts as a sorting factor for targeting of both, cytosolic and transmembrane proteins, to extracellular vesicles. We provide evidence that the SUMO-dependent sorting utilizes the endosomal sorting complex required for transport (ESCRT) by interaction with phosphoinositols. Ubiquitination of cargo proteins is so far the only known determinant for ESCRT-dependent sorting into the extracellular vesicle pathway. Our study reveals a function of SUMO protein modification as a Ubiquitin-independent ESCRT sorting signal, regulating the extracellular vesicle release of α-Synuclein. We deciphered in detail the molecular mechanism which directs α-Synuclein into extracellular vesicles which is of highest relevance for the understanding of Parkinson's disease pathogenesis and progression at the molecular level. We furthermore propose that sumo-dependent sorting constitutes a mechanism with more general implications for cell biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Culture Techniques
  • Cell Line, Tumor
  • Endosomal Sorting Complexes Required for Transport / genetics
  • Endosomal Sorting Complexes Required for Transport / metabolism*
  • Extracellular Vesicles / genetics
  • Extracellular Vesicles / metabolism*
  • Mice
  • Oligodendroglia / cytology*
  • Oligodendroglia / metabolism
  • SUMO-1 Protein / genetics
  • SUMO-1 Protein / metabolism*
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Sumoylation / physiology*
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*


  • Endosomal Sorting Complexes Required for Transport
  • SUMO-1 Protein
  • alpha-Synuclein