Extracellular vesicle sorting of a-Synuclein is regulated by sumoylation

KUNADT M; ECKERMANN K; STUENDL A; GONG J; RUSSO B; STRAUSS K; RAI S; KÜGLER S; FALOMIR LOCKHART L; SCHWALBE M; KRUMOVA P; OLIVEIRA LMA; 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

ACTA NEUROPATHOLOGICA

SPRINGER

Lugar: Berlin; Año: 2015 vol. 129 p. 695 - 713

0001-6322

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.