Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity

Anna Villar-Piqué, Tomás Lopes Da Fonseca, Ricardo Sant'Anna, Éva Mónika Szegö, Luis Fonseca-Ornelas, Raquel Pinho, Anita Carija, Ellen Gerhardt, Caterina Masaracchia, Enrique Abad Gonzalez, Giulia Rossetti, Paolo Carloni, Claudio O. Fernández, Debora Foguel, Ira Milosevic, Markus Zweckstetter, Salvador Ventura, Tiago Fleming Outeiro

Research output: Contribution to journalArticleResearchpeer-review

44 Citations (Scopus)

Abstract

© 2016, National Academy of Sciences. All rights reserved. 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.
Original languageEnglish
Pages (from-to)E6506-E6515
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number42
DOIs
Publication statusPublished - 18 Oct 2016

Keywords

  • Copper
  • H50Q mutation
  • Inclusions
  • Protein aggregation
  • α-synuclein

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