The chaperone-like protein 14-3-3 eta interacts with human alpha-synuclein aggregation intermediates rerouting the amyloidogenic pathway and reducing alpha-synuclein cellular toxicity.

Familial and idiopathic Parkinson’s disease (PD) is associated with the abnormal neuronal accumulation ofa-synuclein (aS) leading tob-sheet-rich aggregates called Lewy Bodies (LBs). Moreover, single point mutationin aS gene and gene multiplication lead to autosomal dominant forms of PD. A connection between PD and the14-3-3 chaperone-like proteins was recently proposed, based on the fact that some of the 14-3-3 isoforms caninteract with genetic PD-associated proteins such as parkin, LRRK2 and aS and were found as components ofLBs in human PD. In particular, a direct interaction between 14-3-3 eta and aS was reported when probed by coimmunoprecipitation from cell models, from parkinsonian brains and by surface plasmon resonance in vitro.However, the mechanisms through which 14-3-3h and aS interact in PD brains remain unclear. Herein, weshow that while 14-3-3 eta is unable to bind monomeric aS, it interacts with aS oligomers which occur duringthe early stages of aS aggregation. Thisinteraction diverts the aggregation process even when 14-3-3 eta is presentin sub-stoichiometric amounts relative to aS. When aS level is overwhelmingly higher than that of 14-3-3 eta, thefibrillation process becomes a sequestration mechanism for 14-3-3 eta, undermining all processes governed bythis protein. Using a panel of complementary techniques, we single out the stage of aggregation at whichthe aS/14-3-3 eta interaction occurs, characterize the products of the resulting processes, and show how theprocesses elucidated in vitro are relevant in cell models. Our findings constitute a first step in elucidating themolecular mechanism of aS/14-3-3 eta interaction and in understanding the critical aggregation step at which14-3-3 eta has the potential to rescue aS-induced cellular toxicity.