Extracellular vesicle sorting of α-Synuclein is regulated by sumoylation

• Autores: Kunadt, Marcel; Eckermann, Katrin; Stuendl, Anne; Gong, Jing; Russo, Belisa; Strauss, Katrin; Rai, Surya; Kügler, Sebastian; Falomir Lockhart, Lisandro Jorge; Schwalbe, Martin; Krumova, Petranka; Oliveira, Luis M. A.; Bähr, Mathias; Möbius, Wiebke; Levin, Johannes; Giese, Armin; Kruse, Niels; Mollenhauer, Brit; Geiss Friedlander, Ruth; Ludolph, Albert C.; Freischmidt, Axel; Feiler, Marisa S.; Danzer, Karin M.; Zweckstetter, Markus; Jovin, Thomas M.; Simons, Mikael; Weishaupt, Jochen H.; Schneider, Anja
• Año de publicación: 2015
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: Biología; Ciencias Médicas; Exosomes; Spreading; Sumoylation; α-Synuclein
• Institución: Universidad Nacional de La Plata

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.
Instituto de Investigaciones Bioquímicas de La Plata