%0 Journal Article
%T Exosomal cell-to-cell transmission of alpha synuclein oligomers
%A Danzer Karin M
%A Kranich Lisa R
%A Ruf Wolfgang P
%A Cagsal-Getkin Ozge
%J Molecular Neurodegeneration
%D 2012
%I BioMed Central
%R 10.1186/1750-1326-7-42
%X Background Aggregation of alpha-synuclein (¦Ásyn) and resulting cytotoxicity is a hallmark of sporadic and familial Parkinson¡¯s disease (PD) as well as dementia with Lewy bodies, with recent evidence implicating oligomeric and pre-fibrillar forms of ¦Ásyn as the pathogenic species. Recent in vitro studies support the idea of transcellular spread of extracellular, secreted ¦Ásyn across membranes. The aim of this study is to characterize the transcellular spread of ¦Ásyn oligomers and determine their extracellular location. Results Using a novel protein fragment complementation assay where ¦Ásyn is fused to non-bioluminescent amino-or carboxy-terminus fragments of humanized Gaussia Luciferase we demonstrate here that ¦Ásyn oligomers can be found in at least two extracellular fractions: either associated with exosomes or free. Exosome-associated ¦Ásyn oligomers are more likely to be taken up by recipient cells and can induce more toxicity compared to free ¦Ásyn oligomers. Specifically, we determine that ¦Ásyn oligomers are present on both the outside as well as inside of exosomes. Notably, the pathway of secretion of ¦Ásyn oligomers is strongly influenced by autophagic activity. Conclusions Our data suggest that ¦Ásyn may be secreted via different secretory pathways. We hypothesize that exosome-mediated release of ¦Ásyn oligomers is a mechanism whereby cells clear toxic ¦Ásyn oligomers when autophagic mechanisms fail to be sufficient. Preventing the early events in ¦Ásyn exosomal release and uptake by inducing autophagy may be a novel approach to halt disease spreading in PD and other synucleinopathies.
%K Alpha synuclein
%K Oligomers
%K Exosomes
%K Parkinson¡¯s disease
%K Aggregation
%K Secretion
%U http://www.molecularneurodegeneration.com/content/7/1/42