TY  - JOUR
AU  - Villar-Piqué, Anna
AU  - Lopes da Fonseca, Tomás
AU  - Sant’Anna, Ricardo
AU  - Szegö, Éva Mónika
AU  - Fonseca-Ornelas, Luis
AU  - Pinho, Raquel
AU  - Carija, Anita
AU  - Gerhardt, Ellen
AU  - Masaracchia, Caterina
AU  - Abad Gonzalez, Enrique
AU  - Rossetti, Giulia
AU  - Carloni, Paolo
AU  - Fernández, Claudio O.
AU  - Foguel, Debora
AU  - Milosevic, Ira
AU  - Zweckstetter, Markus
AU  - Ventura, Salvador
AU  - Outeiro, Tiago Fleming
TI  - Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity
JO  - Proceedings of the National Academy of Sciences of the United States of America
VL  - 113
IS  - 42
SN  - 1091-6490
CY  - Washington, DC
PB  - National Acad. of Sciences
M1  - FZJ-2016-05999
SP  - E6506 - E6515
PY  - 2016
AB  - Synucleinopathies are a group of progressive disorders characterized by the abnormal aggregation and accumulation of α-synuclein (aSyn), an abundant neuronal protein that can adopt different conformations and biological properties. Recently, aSyn pathology was shown to spread between neurons in a prion-like manner. Proteins like aSyn that exhibit self-propagating capacity appear to be able to adopt different stable conformational states, known as protein strains, which can be modulated both by environmental and by protein-intrinsic factors. Here, we analyzed these factors and found that the unique combination of the neurodegeneration-related metal copper and the pathological H50Q aSyn mutation induces a significant alteration in the aggregation properties of aSyn. We compared the aggregation of WT and H50Q aSyn with and without copper, and assessed the effects of the resultant protein species when applied to primary neuronal cultures. The presence of copper induces the formation of structurally different and less-damaging aSyn aggregates. Interestingly, these aggregates exhibit a stronger capacity to induce aSyn inclusion formation in recipient cells, which demonstrates that the structural features of aSyn species determine their effect in neuronal cells and supports a lack of correlation between toxicity and inclusion formation. In total, our study provides strong support in favor of the hypothesis that protein aggregation is not a primary cause of cytotoxicity.
LB  - PUB:(DE-HGF)16
UR  - <Go to ISI:>//WOS:000385610400024
C6  - pmid:27708160
DO  - DOI:10.1073/pnas.1606791113
UR  - https://juser.fz-juelich.de/record/820731
ER  -