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PMID: 25778619 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Acta neuropathologica ·Vol. 129 ·No. 5 ·2015-05-00 ·Pages 695-713

Kunadt M, Eckermann K, Stuendl A, Gong J, Russo B, Strauss K, Rai S, Kügler S, Falomir Lockhart L, Schwalbe M, Krumova P, Oliveira LM, Bähr M, Möbius W, Levin J, Giese A, Kruse N, Mollenhauer B, Geiss-Friedlander R, Ludolph AC, Freischmidt A, Feiler MS, Danzer KM, Zweckstetter M, Jovin TM, Simons M, Weishaupt JH, Schneider A

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.

MeSH Terms
Animals Cell Culture Techniques Cell Line, Tumor Endosomal Sorting Complexes Required for Transport/genetics,metabolism Extracellular Vesicles/genetics,metabolism Mice Oligodendroglia/cytology,metabolism SUMO-1 Protein/genetics,metabolism Signal Transduction/genetics,physiology Sumoylation/physiology alpha-Synuclein/genetics,metabolism
Chemicals
Endosomal Sorting Complexes Required for Transport SUMO-1 Protein alpha-Synuclein
Authors & Affiliations
28 authors, click to expand affiliations / ORCID
Kunadt Marcel
Department of Psychiatry and Psychotherapy, University Medicine Göttingen, Von-Siebold-Str. 5, 37075, Göttingen, Germany.
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
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Article Info
Journal
Acta neuropathologica
Abbr.
Acta Neuropathol
ISSN
1432-0533
DOI
10.1007/s00401-015-1408-1
Published
2015-05-00
Epub
2015-00-17
Pages
695-713
Language
English
Region
Germany
NLM ID
0412041
PMCID
PMC4405286
Subset
IM
External Links
PubMed source DOI: 10.1007/s00401-015-1408-1 PMC Full Text View journal details
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