Journal Article

DZNE-2020-04205

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Extracellular vesicle sorting of α-Synuclein is regulated by sumoylation.

Kunadt, M. ; Eckermann, K. ; Stuendl, A. ; Gong, J.DZNE* ; Russo, B.DZNE* ; Strauss, K. ; Rai, S. ; Kügler, S. ; Falomir Lockhart, L. ; Schwalbe, M. ; Krumova, P. ; Oliveira, L. M. A. ; Bähr, M. ; Möbius, W. ; Levin, J. ; Giese, A. ; Kruse, N. ; Mollenhauer, B.Extern* ; Geiss-Friedlander, R. ; Ludolph, A. C. ; Freischmidt, A. ; Feiler, M. S. ; Danzer, K. M.Extern* ; Zweckstetter, M.DZNE* ; Jovin, T. M. ; Simons, M. ; Weishaupt, J. H. ; Schneider, A. (Last author)DZNE*

2015
Springer Heidelberg

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Please use a persistent id in citations: doi:10.1007/s00401-015-1408-1

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.

Keyword(s): Animals (MeSH) ; Cell Culture Techniques (MeSH) ; Cell Line, Tumor (MeSH) ; Endosomal Sorting Complexes Required for Transport: genetics (MeSH) ; Endosomal Sorting Complexes Required for Transport: metabolism (MeSH) ; Extracellular Vesicles: genetics (MeSH) ; Extracellular Vesicles: metabolism (MeSH) ; Mice (MeSH) ; Oligodendroglia: cytology (MeSH) ; Oligodendroglia: metabolism (MeSH) ; SUMO-1 Protein: genetics (MeSH) ; SUMO-1 Protein: metabolism (MeSH) ; Signal Transduction: genetics (MeSH) ; Signal Transduction: physiology (MeSH) ; Sumoylation: physiology (MeSH) ; alpha-Synuclein: genetics (MeSH) ; alpha-Synuclein: metabolism (MeSH) ; Endosomal Sorting Complexes Required for Transport ; SUMO-1 Protein ; alpha-Synuclein

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Contributing Institute(s):

1. Translational Dementia Research Göttingen (AG Schneider Göttingen)
2. Translational Structural Biology (AG Zweckstetter)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)
2. 344 - Clinical and Health Care Research (POF3-344) (POF3-344)

Appears in the scientific report 2015

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