TY  - JOUR
AU  - Kunadt, Marcel
AU  - Eckermann, Katrin
AU  - Stuendl, Anne
AU  - Gong, Jing
AU  - Russo, Belisa
AU  - Strauss, Katrin
AU  - Rai, Surya
AU  - Kügler, Sebastian
AU  - Falomir Lockhart, Lisandro
AU  - Schwalbe, Martin
AU  - Krumova, Petranka
AU  - Oliveira, Luis M A
AU  - Bähr, Mathias
AU  - Möbius, Wiebke
AU  - Levin, Johannes
AU  - Giese, Armin
AU  - Kruse, Niels
AU  - Mollenhauer, Brit
AU  - Geiss-Friedlander, Ruth
AU  - Ludolph, Albert C
AU  - Freischmidt, Axel
AU  - Feiler, Marisa S
AU  - Danzer, Karin M
AU  - Zweckstetter, Markus
AU  - Jovin, Thomas M
AU  - Simons, Mikael
AU  - Weishaupt, Jochen H
AU  - Schneider, Anja
TI  - Extracellular vesicle sorting of α-Synuclein is regulated by sumoylation.
JO  - Acta neuropathologica
VL  - 129
IS  - 5
SN  - 0001-6322
CY  - Heidelberg
PB  - Springer
M1  - DZNE-2020-04205
SP  - 695-713
PY  - 2015
AB  - 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.
KW  - Animals
KW  - Cell Culture Techniques
KW  - Cell Line, Tumor
KW  - Endosomal Sorting Complexes Required for Transport: genetics
KW  - Endosomal Sorting Complexes Required for Transport: metabolism
KW  - Extracellular Vesicles: genetics
KW  - Extracellular Vesicles: metabolism
KW  - Mice
KW  - Oligodendroglia: cytology
KW  - Oligodendroglia: metabolism
KW  - SUMO-1 Protein: genetics
KW  - SUMO-1 Protein: metabolism
KW  - Signal Transduction: genetics
KW  - Signal Transduction: physiology
KW  - Sumoylation: physiology
KW  - alpha-Synuclein: genetics
KW  - alpha-Synuclein: metabolism
KW  - Endosomal Sorting Complexes Required for Transport (NLM Chemicals)
KW  - SUMO-1 Protein (NLM Chemicals)
KW  - alpha-Synuclein (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25778619
C2  - pmc:PMC4405286
DO  - DOI:10.1007/s00401-015-1408-1
UR  - https://pub.dzne.de/record/137883
ER  -