title: Extracellular vesicle sorting of α-Synuclein is regulated by sumoylation.
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.
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medicine Göttingen, Von-Siebold-Str. 5, 37075, Göttingen, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kunadt
authors.forename: Katrin
authors.initials: K
authors.lastname: Eckermann
authors.forename: Anne
authors.initials: A
authors.lastname: Stuendl
authors.forename: Jing
authors.initials: J
authors.lastname: Gong
authors.forename: Belisa
authors.initials: B
authors.lastname: Russo
authors.forename: Katrin
authors.initials: K
authors.lastname: Strauss
authors.forename: Surya
authors.initials: S
authors.lastname: Rai
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kügler
authors.forename: Lisandro
authors.initials: L
authors.lastname: Falomir Lockhart
authors.forename: Martin
authors.initials: M
authors.lastname: Schwalbe
authors.forename: Petranka
authors.initials: P
authors.lastname: Krumova
authors.forename: Luis M A
authors.initials: LM
authors.lastname: Oliveira
authors.forename: Mathias
authors.initials: M
authors.lastname: Bähr
authors.forename: Wiebke
authors.initials: W
authors.lastname: Möbius
authors.forename: Johannes
authors.initials: J
authors.lastname: Levin
authors.forename: Armin
authors.initials: A
authors.lastname: Giese
authors.forename: Niels
authors.initials: N
authors.lastname: Kruse
authors.forename: Brit
authors.initials: B
authors.lastname: Mollenhauer
authors.forename: Ruth
authors.initials: R
authors.lastname: Geiss-Friedlander
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.forename: Axel
authors.initials: A
authors.lastname: Freischmidt
authors.forename: Marisa S
authors.initials: MS
authors.lastname: Feiler
authors.forename: Karin M
authors.initials: KM
authors.lastname: Danzer
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Jovin
authors.forename: Mikael
authors.initials: M
authors.lastname: Simons
authors.forename: Jochen H
authors.initials: JH
authors.lastname: Weishaupt
authors.forename: Anja
authors.initials: A
authors.lastname: Schneider
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D000067128:Extracellular Vesicles / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009836:Oligodendroglia / Q000166:cytology* / Q000378:metabolism; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D058207:Sumoylation / Q000502:physiology*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D025842:SUMO-1 Protein; D051844:alpha-Synuclein