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

Villar-Piqué, A., da Fonseca, T. L., Sant’Anna, R., Szegö, E. M., Fonseca-Ornelas, L., Pinho, R., et al. (2016). Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity. Proceedings of the National Academy of Sciences of the United States of Amerca, 113(42), E6506-E6515. doi:10.1073/pnas.1606791113.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002B-A242-D Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-28E8-0
Genre: Journal Article

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Villar-Piqué, A., Author
da Fonseca, T. L., Author
Sant’Anna, R., Author
Szegö, E. M., Author
Fonseca-Ornelas, L.1, Author              
Pinho, R., Author
Carija, A., Author
Gerhardt, E., Author
Masaracchia, C., Author
Gonzalezf, E. A., Author
Rossetti, G., Author
Carloni, P., Author
Fernández, C. O., Author
Foguel, D., Author
Milosevic, I., Author
Zweckstetter, M.1, Author              
Ventura, S., Author
Outeiro, T. F., Author
Affiliations:
1Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              

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Free keywords: α-synuclein; Copper; H50Q mutation; Inclusions; Protein aggregation
 Abstract: 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.

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Language(s): eng - English
 Dates: 2016-10-05
 Publication Status: Published online
 Pages: -
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 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1073/pnas.1606791113
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Title: Proceedings of the National Academy of Sciences of the United States of Amerca
Source Genre: Journal
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Pages: - Volume / Issue: 113 (42) Sequence Number: - Start / End Page: E6506 - E6515 Identifier: -