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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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Main Authors: Kunadt, Marcel (Author) , Eckermann, Katrin (Author) , Stuendl, Anne (Author) , Gong, Jing (Author) , Russo, Belisa (Author) , Strauß, Katrin (Author) , Rai, Surya (Author) , Kügler, Sebastian (Author) , Falomir Lockhart, Lisandro (Author) , Schwalbe, Martin (Author) , Krumova, Petranka (Author) , Oliveira, Luis M. A. (Author) , Bähr, Mathias (Author) , Möbius, Wiebke (Author) , Levin, Johannes Martin (Author) , Giese, Armin (Author) , Kruse, Niels (Author) , Mollenhauer, Brit (Author) , Geiss-Friedlander, Ruth (Author) , Ludolph, Albert C. (Author) , Freischmidt, Axel (Author) , Feiler, Marisa S. (Author) , Danzer, Karin M. (Author) , Zweckstetter, Markus (Author) , Jovin, Thomas M. (Author) , Simons, Mikael (Author) , Weishaupt, Jochen H. (Author) , Schneider, Anja (Author)
Format: Article (Journal)
Language:English
Published: 17 March 2015
In: Acta neuropathologica
Year: 2015, Volume: 129, Issue: 5, Pages: 695-713
ISSN:1432-0533
DOI:10.1007/s00401-015-1408-1
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1007/s00401-015-1408-1
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Author Notes:Marcel Kunadt, Katrin Eckermann, Anne Stuendl, Jing Gong, Belisa Russo, Katrin Strauss, Surya Rai, Sebastian Kügler, Lisandro Falomir Lockhart, Martin Schwalbe, Petranka Krumova, Luis M.A. Oliveira, Mathias Bähr, Wiebke Möbius, Johannes Levin, Armin Giese, Niels Kruse, Brit Mollenhauer, Ruth Geiss-Friedlander, Albert C. Ludolph, Axel Freischmidt, Marisa S. Feiler, Karin M. Danzer, Markus Zweckstetter, Thomas M. Jovin, Mikael Simons, Jochen H. Weishaupt, Anja Schneider
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Summary: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.
Item Description:Gesehen am 29.07.2021
Physical Description:Online Resource
ISSN:1432-0533
DOI:10.1007/s00401-015-1408-1

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