Exosomal cell-to-cell transmission of alpha synuclein oligomers

Karin M. Danzer, Lisa R. Kranich, Wolfgang P. Ruf, Ozge Cagsal-Getkin, Ashley R. Winslow, Liya Zhu, Charles R. Vanderburg, Pamela J. McLean

Research output: Contribution to journalArticle

376 Scopus citations

Abstract

Background: Aggregation of alpha-synuclein (syn) and resulting cytotoxicity is a hallmark of sporadic and familial Parkinsons disease (PD) as well as dementia with Lewy bodies, with recent evidence implicating oligomeric and pre-fibrillar forms of syn as the pathogenic species. Recent in vitro studies support the idea of transcellular spread of extracellular, secreted syn across membranes. The aim of this study is to characterize the transcellular spread of syn oligomers and determine their extracellular location. Results: Using a novel protein fragment complementation assay where syn is fused to non-bioluminescent amino-or carboxy-terminus fragments of humanized Gaussia Luciferase we demonstrate here that syn oligomers can be found in at least two extracellular fractions: either associated with exosomes or free. Exosome-associated syn oligomers are more likely to be taken up by recipient cells and can induce more toxicity compared to free syn oligomers. Specifically, we determine that syn oligomers are present on both the outside as well as inside of exosomes. Notably, the pathway of secretion of syn oligomers is strongly influenced by autophagic activity. Conclusions: Our data suggest that syn may be secreted via different secretory pathways. We hypothesize that exosome-mediated release of syn oligomers is a mechanism whereby cells clear toxic syn oligomers when autophagic mechanisms fail to be sufficient. Preventing the early events in syn exosomal release and uptake by inducing autophagy may be a novel approach to halt disease spreading in PD and other synucleinopathies.

Original languageEnglish (US)
Article number42
JournalMolecular neurodegeneration
Volume7
Issue number1
DOIs
StatePublished - Aug 28 2012

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Keywords

  • Aggregation
  • Alpha synuclein
  • Exosomes
  • Oligomers
  • Parkinsons disease
  • Secretion

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Danzer, K. M., Kranich, L. R., Ruf, W. P., Cagsal-Getkin, O., Winslow, A. R., Zhu, L., Vanderburg, C. R., & McLean, P. J. (2012). Exosomal cell-to-cell transmission of alpha synuclein oligomers. Molecular neurodegeneration, 7(1), [42]. https://doi.org/10.1186/1750-1326-7-42