title: The chaperone-like protein 14-3-3η interacts with human α-synuclein aggregation intermediates rerouting the amyloidogenic pathway and reducing α-synuclein cellular toxicity.
abstract: Familial and idiopathic Parkinson's disease (PD) is associated with the abnormal neuronal accumulation of α-synuclein (aS) leading to β-sheet-rich aggregates called Lewy Bodies (LBs). Moreover, single point mutation in aS gene and gene multiplication lead to autosomal dominant forms of PD. A connection between PD and the 14-3-3 chaperone-like proteins was recently proposed, based on the fact that some of the 14-3-3 isoforms can interact with genetic PD-associated proteins such as parkin, LRRK2 and aS and were found as components of LBs in human PD. In particular, a direct interaction between 14-3-3η and aS was reported when probed by co-immunoprecipitation from cell models, from parkinsonian brains and by surface plasmon resonance in vitro. However, the mechanisms through which 14-3-3η and aS interact in PD brains remain unclear. Herein, we show that while 14-3-3η is unable to bind monomeric aS, it interacts with aS oligomers which occur during the early stages of aS aggregation. This interaction diverts the aggregation process even when 14-3-3η is present in sub-stoichiometric amounts relative to aS. When aS level is overwhelmingly higher than that of 14-3-3η, the fibrillation process becomes a sequestration mechanism for 14-3-3η, undermining all processes governed by this protein. Using a panel of complementary techniques, we single out the stage of aggregation at which the aS/14-3-3η interaction occurs, characterize the products of the resulting processes, and show how the processes elucidated in vitro are relevant in cell models. Our findings constitute a first step in elucidating the molecular mechanism of aS/14-3-3η interaction and in understanding the critical aggregation step at which 14-3-3η has the potential to rescue aS-induced cellular toxicity.
authors.affiliation: Department of Biology and.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Plotegher
authors.affiliation: Department of Biochemistry, University of Bologna, Bologna, Italy.
authors.forename: Dhruv
authors.initials: D
authors.lastname: Kumar
authors.affiliation: Department of Biology and.
authors.forename: Isabella
authors.initials: I
authors.lastname: Tessari
authors.affiliation: Department of Biochemistry, University of Bologna, Bologna, Italy, ISMN-National Council of Research, Rome, Italy and.
authors.forename: Marco
authors.initials: M
authors.lastname: Brucale
authors.affiliation: Department of Chemical Sciences, University of Padova, Padova, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Munari
authors.affiliation: Department of Biology and.
authors.forename: Laura
authors.initials: L
authors.lastname: Tosatto
authors.affiliation: Department of Biology and.
authors.forename: Elisa
authors.initials: E
authors.lastname: Belluzzi
authors.affiliation: Department of Biology and.
authors.forename: Elisa
authors.initials: E
authors.lastname: Greggio
authors.affiliation: Department of Biology and.
authors.forename: Marco
authors.initials: M
authors.lastname: Bisaglia
authors.affiliation: Department of Biotechnology, University of Verona, Verona, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Capaldi
authors.affiliation: Department of Biochemistry, University of Bologna, Bologna, Italy.
authors.forename: Daniel
authors.initials: D
authors.lastname: Aioanei
authors.affiliation: Department of Chemical Sciences, University of Padova, Padova, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Mammi
authors.affiliation: Department of Biotechnology, University of Verona, Verona, Italy.
authors.forename: Hugo L
authors.initials: HL
authors.lastname: Monaco
authors.affiliation: Department of Biochemistry, University of Bologna, Bologna, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Samo
authors.affiliation: Department of Biology and luigi.bubacco@unipd.it.
authors.forename: Luigi
authors.initials: L
authors.lastname: Bubacco
mesh_terms: D048948:14-3-3 Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000686:Amyloidosis / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D066263:Protein Aggregation, Pathological; D011485:Protein Binding; D020033:Protein Isoforms; D015398:Signal Transduction; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; D020033:Protein Isoforms; D051844:alpha-Synuclein