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000820731 0247_ $$2doi$$a10.1073/pnas.1606791113
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000820731 1001_ $$0P:(DE-HGF)0$$aVillar-Piqué, Anna$$b0
000820731 245__ $$aEnvironmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity
000820731 260__ $$aWashington, DC$$bNational Acad. of Sciences$$c2016
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000820731 520__ $$aSynucleinopathies 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.
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000820731 7001_ $$0P:(DE-HGF)0$$aLopes da Fonseca, Tomás$$b1
000820731 7001_ $$0P:(DE-HGF)0$$aSant’Anna, Ricardo$$b2
000820731 7001_ $$0P:(DE-HGF)0$$aSzegö, Éva Mónika$$b3
000820731 7001_ $$0P:(DE-HGF)0$$aFonseca-Ornelas, Luis$$b4
000820731 7001_ $$0P:(DE-HGF)0$$aPinho, Raquel$$b5
000820731 7001_ $$0P:(DE-HGF)0$$aCarija, Anita$$b6
000820731 7001_ $$0P:(DE-HGF)0$$aGerhardt, Ellen$$b7
000820731 7001_ $$0P:(DE-HGF)0$$aMasaracchia, Caterina$$b8
000820731 7001_ $$0P:(DE-HGF)0$$aAbad Gonzalez, Enrique$$b9
000820731 7001_ $$0P:(DE-Juel1)145921$$aRossetti, Giulia$$b10$$ufzj
000820731 7001_ $$0P:(DE-Juel1)145614$$aCarloni, Paolo$$b11$$ufzj
000820731 7001_ $$0P:(DE-HGF)0$$aFernández, Claudio O.$$b12
000820731 7001_ $$0P:(DE-HGF)0$$aFoguel, Debora$$b13
000820731 7001_ $$0P:(DE-HGF)0$$aMilosevic, Ira$$b14
000820731 7001_ $$0P:(DE-HGF)0$$aZweckstetter, Markus$$b15
000820731 7001_ $$0P:(DE-HGF)0$$aVentura, Salvador$$b16
000820731 7001_ $$0P:(DE-HGF)0$$aOuteiro, Tiago Fleming$$b17$$eCorresponding author
000820731 773__ $$0PERI:(DE-600)1461794-8$$a10.1073/pnas.1606791113$$gVol. 113, no. 42, p. E6506 - E6515$$n42$$pE6506 - E6515$$tProceedings of the National Academy of Sciences of the United States of America$$v113$$x1091-6490$$y2016
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