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Extracellular vesicle sorting of α-Synuclein is regulated by sumoylation

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 fin...

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Detalles Bibliográficos
Autores principales: Kunadt, Marcel, Eckermann, Katrin, Stuendl, Anne, Gong, Jing, Russo, Belisa, Strauss, Katrin, Rai, Surya, Kügler, Sebastian, Falomir Lockhart, Lisandro, 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405286/
https://www.ncbi.nlm.nih.gov/pubmed/25778619
http://dx.doi.org/10.1007/s00401-015-1408-1
Descripción
Sumario: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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00401-015-1408-1) contains supplementary material, which is available to authorized users.