Extracellular vesicle sorting of α-Synuclein is regulated by sumoylation.
Acta Neuropathol
; 129(5): 695-713, 2015 May.
Article
em En
| MEDLINE
| ID: mdl-25778619
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Oligodendroglia
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Proteína SUMO-1
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Alfa-Sinucleína
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Complexos Endossomais de Distribuição Requeridos para Transporte
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Sumoilação
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Vesículas Extracelulares
Limite:
Animals
Idioma:
En
Revista:
Acta Neuropathol
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Alemanha