Journal Article

Extracellular vesicle sorting of α-Synuclein is regulated by sumoylation

Russo, Belisa, Ludolph, Albert C., Schwalbe, Martin, Geiss-Friedlander, Ruth, Feiler, Marisa S., Bähr, Mathias, Schneider, Anja, Rai, Surya, Giese, Armin, Zweckstetter, Markus, Stuendl, Anne, Simons, Mikael, Jovin, Thomas M., Freischmidt, Axel, Danzer, Karin M., Mollenhauer, Brit, Oliveira, Luis M. A., Strauss, Katrin, Gong, Jing, Levin, Johannes, Möbius, Wiebke, Weishaupt, Jochen H., Kruse, Niels, Krumova, Petranka, Kunadt, Marcel, Kügler, Sebastian, Falomir Lockhart, Lisandro, Eckermann, Katrin

2015

Overview

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.

• Publisher: Springer Berlin Heidelberg
• Subject: alpha-Synuclein - genetics / alpha-Synuclein - metabolism / 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 / Medicine / Medicine & Public Health / Mice / Neurosciences / Oligodendroglia - cytology / Oligodendroglia - metabolism / Original Paper / Pathology / Signal Transduction - genetics / Signal Transduction - physiology / SUMO-1 Protein - genetics / SUMO-1 Protein - metabolism / Sumoylation - physiology