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  Extracellular vesicle sorting of α-Synuclein is regulated by sumoylation.

Kunadt, M., Eckermann, K., Stuendl, A., Gong, J., Russo, B., Strauss, K., et al. (2015). Extracellular vesicle sorting of α-Synuclein is regulated by sumoylation. Acta Neuropathologica, 129(5), 695-713. doi:10.1007/s00401-015-1408-1.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0025-AA48-9 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-CD0B-4
Genre: Journal Article

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 Creators:
Kunadt, M., Author
Eckermann, K., Author
Stuendl, A., Author
Gong, J., Author
Russo, B., Author
Strauss, K., Author
Rai, S., Author
Kügler, S., Author
Falomir Lockhart, L. J.1, Author              
Schwalbe, M.2, Author              
Krumova, P., Author
Oliveira, L. M. A., Author
Bähr, M., Author
Möbius, W., Author
Levin, J., Author
Giese, A., Author
Kruse, N., Author
Mollenhauer, B., Author
Geiss-Friedlander, R., Author
Ludolph, A. C., Author
Freischmidt, A., AuthorFeiler, M. S., AuthorDanzer, K. M., AuthorZweckstetter, M.2, Author              Jovin, T. M.1, Author              Simons, M., AuthorWeishaupt, J. H., AuthorSchneider, A., Author more..
Affiliations:
1Emeritus Group Laboratory of Cellular Dynamics, MPI for biophysical chemistry, Max Planck Society, ou_578628              
2Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              

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 Abstract: 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.

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Language(s): eng - English
 Dates: 2015-03-172015-05
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1007/s00401-015-1408-1
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Title: Acta Neuropathologica
Source Genre: Journal
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Pages: - Volume / Issue: 129 (5) Sequence Number: - Start / End Page: 695 - 713 Identifier: -