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Acceleration of α-synuclein aggregation by exosomes

In English

Författare

  • Marie Grey
  • Christopher Dunning
  • Ricardo Gaspar
  • Carl Grey
  • Patrik Brundin
  • Emma Sparr
  • Sara Linse

Summary, in English

Exosomes are small vesicles released from cells into extra-cellular space. We have isolated exosomes from neuroblastoma cells and investigated their influence on the aggregation of α-synuclein, a protein associated with Parkinson disease pathology. Using cryo-transmission electron microscopy of exosomes we found spherical unilamellar vesicles with a significant protein content, and Western blot analysis revealed that they contain, as expected, the proteins flotillin-1 and alix. Using thioflavin T fluorescence to monitor aggregation kinetics, we found that exosomes catalyze the process in a similar manner as low concentration of preformed α-synuclein fibrils. The exosomes reduce the lag time indicating that they provide catalytic environments for nucleation. The catalytic effect of exosomes derived from naive cells and cells that over-express α-synuclein do not differ. Vesicles prepared from extracted exosome lipids accelerate aggregation, suggesting that the lipids in exosomes are sufficient for the catalytic effect to arise. Using mass spectrometry we found several phospholipid classes in the exosomes, including phosphatidyl choline, phosphatidyl serine, phosphatidyl ethanolamine, phosphatidyl inositol and the gangliosides GM2 and GM3. Within each class, several species with different acyl chains were identified. We then prepared vesicles from corresponding pure lipids or defined mixtures, most of which were found to retard α-synuclein aggregation. As a striking exception, vesicles containing ganglioside lipids GM1 or GM3 accelerate the process. Understanding how α-synuclein interacts with biological membranes to promote neurological disease might lead to the identification of novel therapeutic targets.

Publiceringsår

2015

Språk

Engelska

Sidor

2969-2982

Publikation/Tidskrift/Serie

Journal of Biological Chemistry

Volym

290

Issue

5

Dokumenttyp

Artikel i tidskrift

Förlag

American Society for Biochemistry and Molecular Biology

Ämne

  • Neurosciences
  • Basic Medicine

Status

Published

ISBN/ISSN/Övrigt

  • ISSN: 1083-351X