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

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Falomir Lockhart,  L. J.
Emeritus Group Laboratory of Cellular Dynamics, MPI for biophysical chemistry, Max Planck Society;

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Schwalbe,  M.
Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society;

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Zweckstetter,  M.
Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society;

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Jovin,  T. M.
Emeritus Group Laboratory of Cellular Dynamics, MPI for biophysical chemistry, Max Planck Society;

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Citation

Kunadt, M., Eckermann, K., Stuendl, A., Gong, J., Russo, B., Strauss, K., et al. (2015). Extracellular vesicle sorting of α-Synuclein is regulated by sumoylation. Acta Neuropathologica, 129(5), 695-713. doi:10.1007/s00401-015-1408-1.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0025-AA48-9
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.