Extracellular vesicle sorting of α-Synuclein is regulated by sumoylation

Authors
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
Publication Year
2015
Language
English
Format
article
Status
Published version
Description
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.
Fil: Kunadt, Marcel. Universität Göttingen; Alemania. Nanoscale Microscopy and Molecular Physiology of the Brain; Alemania. Max-Planck-Institute for Experimental Medicine; Alemania
Fil: Eckermann, Katrin. Nanoscale Microscopy and Molecular Physiology of the Brain; Alemania
Fil: Stuendl, Anne. Universität Göttingen; Alemania
Fil: Gong, Jing. Max-Planck-Institute for Experimental Medicine; Alemania
Fil: Russo, Belisa. Max-Planck-Institute for Experimental Medicine; Alemania
Fil: Strauss, Katrin. Universität Göttingen; Alemania. Nanoscale Microscopy and Molecular Physiology of the Brain; Alemania
Fil: Rai, Surya. Universität Göttingen; Alemania
Fil: Kügler, Sebastian. Nanoscale Microscopy and Molecular Physiology of the Brain; Alemania
Fil: Falomir Lockhart, Lisandro Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata ; Argentina. Max-Planck-Institute for Biophysical Chemistry; Alemania
Fil: Schwalbe, Martin. Max-Planck-Institute for Biophysical Chemistry; Alemania
Fil: Krumova, Petranka. University Medicine Göttingen; Alemania
Fil: Oliveira, Luis M. A.. Max-Planck-Institute for Biophysical Chemistry; Alemania
Fil: Bähr, Mathias. Nanoscale Microscopy and Molecular Physiology of the Brain; Alemania
Fil: Möbius, Wiebke. Nanoscale Microscopy and Molecular Physiology of the Brain; Alemania
Fil: Levin, Johannes. Ludwig-Maximilians-University; Alemania
Fil: Giese, Armin. Ludwig-Maximilians-University; Alemania
Fil: Kruse, Niels. University Medicine Göttingen; Alemania
Fil: Mollenhauer, Brit. University Medicine Göttingen; Alemania
Fil: Geiss Friedlander, Ruth. University Medicine Göttingen; Alemania
Fil: Ludolph, Albert C.. Ulm University; Alemania
Fil: Freischmidt, Axel. Ulm University; Alemania
Fil: Feiler, Marisa S.. Ulm University; Alemania
Fil: Danzer, Karin M.. Ulm University; Alemania
Fil: Zweckstetter, Markus. Nanoscale Microscopy and Molecular Physiology of the Brain; Alemania
Fil: Jovin, Thomas M.. Nanoscale Microscopy and Molecular Physiology of the Brain; Alemania
Fil: Simons, Mikael. Nanoscale Microscopy and Molecular Physiology of the Brain; Alemania
Fil: Weishaupt, Jochen H.. Nanoscale Microscopy and Molecular Physiology of the Brain; Alemania
Fil: Schneider, Anja. Universität Göttingen; Alemania. Nanoscale Microscopy and Molecular Physiology of the Brain; Alemania
Subject
EXOSOMES
SPREADING
SUMOYLATION
Α-SYNUCLEIN
Otras Ciencias Biológicas
Ciencias Biológicas
CIENCIAS NATURALES Y EXACTAS
Access level
Open access
License
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repository
CONICET Digital (CONICET)
Institution
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identifier
oai:ri.conicet.gov.ar:11336/51660