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

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.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

Villar-Piqué A,Lopes da Fonseca T,Sant'Anna R,Szegö ÉM,Fonseca-Ornelas L,Pinho R,Carija A,Gerhardt E,Masaracchia C,Abad Gonzalez E,Rossetti G,Carloni P,Fernández CO,Foguel D,Milosevic I,Zweckstetter M,Ventura S,Outeiro

doi

10.1073/pnas.1606791113

subject

Has Abstract

pub_date

2016-10-18 00:00:00

pages

E6506-E6515

issue

42

eissn

0027-8424

issn

1091-6490

pii

1606791113

journal_volume

113

pub_type

杂志文章

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