Single-molecule FRET studies on alpha-synuclein oligomerization of Parkinson's disease genetically related mutants

Tosatto, L. ; Horrocks, M.H. ; Dear, A.J. ; Knowles, T.P.J. ; Dalla Serra, M. ; Cremades, N. (Universidad de Zaragoza) ; Dobson, C.M. ; Klenerman, D.

Resumen: Oligomers of alpha-synuclein are toxic to cells and have been proposed to play a key role in the etiopathogenesis of Parkinson''s disease. As certain missense mutations in the gene encoding for alpha-synuclein induce early-onset forms of the disease, it has been suggested that these variants might have an inherent tendency to produce high concentrations of oligomers during aggregation, although a direct experimental evidence for this is still missing. We used single-molecule Förster Resonance Energy Transfer to visualize directly the protein self-assembly process by wild-type alpha-synuclein and A53T, A30P and E46K mutants and to compare the structural properties of the ensemble of oligomers generated. We found that the kinetics of oligomer formation correlates with the natural tendency of each variant to acquire beta-sheet structure. Moreover, A53T and A30P showed significant differences in the averaged FRET efficiency of one of the two types of oligomers formed compared to the wild-type oligomers, indicating possible structural variety among the ensemble of species generated. Importantly, we found similar concentrations of oligomers during the lag-phase of the aggregation of wild-type and mutated alpha-synuclein, suggesting that the properties of the ensemble of oligomers generated during self-assembly might be more relevant than their absolute concentration for triggering neurodegeneration.

Idioma: Inglés

DOI: 10.1038/srep16696

Año: 2015

Publicado en: Scientific Reports 5 (2015), 16696 [12 pp]
ISSN: 2045-2322

Factor impacto JCR: 5.228 (2015)

Categ. JCR: MULTIDISCIPLINARY SCIENCES rank: 7 / 62 = 0.113 (2015) - Q1 - T1

Factor impacto SCIMAGO: 2.034 - Multidisciplinary (Q1)

Tipo y forma: Article (Published version)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)