The Pathological G51D Mutation in Alpha-Synuclein Oligomers Confers Distinct Structural Attributes and Cellular Toxicity

Xu, Catherine K. ; Castellana-Cruz, Marta ; Chen, Serene W. ; Du, Zhen ; Meisl, Georg ; Levin, Aviad ; Mannini, Benedetta ; Itzhaki, Laura ; Knowles, Tuomas P. J. ; Dobson, Christopher ; Cremades, Nunilo (Universidad de Zaragoza) ; Kumita, Janet R.

Resumen: A wide variety of oligomeric structures are formed during the aggregation of proteins associated with neurodegenerative diseases. Such soluble oligomers are believed to be key toxic species in the related disorders; therefore, identification of the structural determinants of toxicity is of upmost importance. Here, we analysed toxic oligomers of α-synuclein and its pathological variants in order to identify structural features that could be related to toxicity and found a novel structural polymorphism within G51D oligomers. These G51D oligomers can adopt a variety of β-sheet-rich structures with differing degrees of α-helical content, and the helical structural content of these oligomers correlates with the level of induced cellular dysfunction in SH-SY5Y cells. This structure–function relationship observed in α-synuclein oligomers thus presents the α-helical structure as another potential structural determinant that may be linked with cellular toxicity in amyloid-related proteins.

Idioma: Inglés

DOI: 10.3390/molecules27041293

Año: 2022

Publicado en: Molecules 27, 4 (2022), 1293 [14 pp.]
ISSN: 1420-3049

Factor impacto JCR: 4.6 (2022)

Categ. JCR: CHEMISTRY, MULTIDISCIPLINARY rank: 63 / 178 = 0.354 (2022) - Q2 - T2
Categ. JCR: BIOCHEMISTRY & MOLECULAR BIOLOGY rank: 97 / 285 = 0.34 (2022) - Q2 - T2

Factor impacto CITESCORE: 6.7 - Biochemistry, Genetics and Molecular Biology (Q2) - Chemistry (Q1) - Pharmacology, Toxicology and Pharmaceutics (Q2)

Factor impacto SCIMAGO: 0.704 - Pharmaceutical Science (Q1) - Chemistry (miscellaneous) (Q2) - Drug Discovery (Q2) - Physical and Theoretical Chemistry (Q2) - Organic Chemistry (Q2) - Analytical Chemistry (Q2) - Medicine (miscellaneous) (Q2) - Molecular Medicine (Q3)

Financiación: info:eu-repo/grantAgreement/ES/MCIU-FEDER/PGC2018-096335-B-100
Financiación: info:eu-repo/grantAgreement/ES/MINECO/RYC-2012-12068

Tipo y forma: Article (Published version)

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