Dimerization propensities of Synucleins are not predictive for Synuclein aggregation

Abstract

Aggregation and fibril formation of human alpha-Synuclein (alpha S) are neuropathological hallmarks of Parkinson's disease and other synucleinopathies. The molecular mechanisms of alpha S aggregation and fibrillogenesis are largely unknown. Several studies suggested a sequence of events from alpha S dimerization via oligomerization and pre-fibrillar aggregation to alpha S fibril formation. In contrast to alpha S, little evidence suggests that gamma S can form protein aggregates in the brain, and for beta S its neurotoxic properties and aggregation propensities are controversially discussed. These apparent differences in aggregation behavior prompted us to investigate the first step in Synuclein aggregation, i.e. the formation of dimers or oligomers, by Bimolecular Fluorescence Complementation in cells. This assay showed some Synuclein-specific limitations, questioning its performance on a single cell level. Nevertheless, we unequivocally demonstrate that all Synucleins can interact with each other in a very similar way. Given the divergent aggregation properties of the three Synucleins this suggests that formation of dimers is not predictive for the aggregation of alpha S, beta S or gamma S in the aged or diseased brain. (C) 2015 Elsevier B.V. All rights reserved.