10.3390/molecules27041293 The Pathological G51D Mutation in Alpha-Synuclein Oligomers Confers Distinct Structural Attributes and Cellular Toxicity http://orcid.org/ Xu Catherine Dr. Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK catherine.xu@mpl.mpg.de http://orcid.org/ Castellana-Cruz Marta Dr. Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK mc2033@cam.ac.uk http://orcid.org/ Chen Serene Dr. Department of Life Sciences, South Kensington Campus, Imperial College London, London SW7 2AZ, UK weiyan89@gmail.com http://orcid.org/ Du Zhen Dr. Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK zhen_du2020@163.com http://orcid.org/0000-0002-6562-7715 Meisl Georg Dr. Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK gm373@cam.ac.uk http://orcid.org/ Levin Aviad Dr. Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK al680@cam.ac.uk http://orcid.org/0000-0001-6812-7348 Mannini Benedetta Dr. Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK bm475@cam.ac.uk http://orcid.org/0000-0001-6504-2576 Itzhaki Laura Dr. Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK lsi10@cam.ac.uk http://orcid.org/ Knowles Tuomas Dr. Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK Cavendish Laboratory, Department of Physics, University of Cambridge, JJ Thomson Avenue, Cambridge CB3 0HE, UK tpjk2@cam.ac.uk http://orcid.org/ Dobson Christopher Dr. Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK http://orcid.org/ Cremades Nunilo Dr. Institute for Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza, Mariano Esquillor, Edificio I+D+I, 50018 Zaragoza, Spain ncc@unizar.es http://orcid.org/0000-0002-3887-4964 Kumita Janet Dr. Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK jrk38@cam.ac.uk 15 02 2022 27 4 10 02 2022 e1293 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. Wellcome Trust 094425/Z/10/Z Medical Research Council MR/W01632X/1 © 1996-2022 MDPI (Basel, Switzerland) 2022 This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited α-synuclein toxic oligomers Parkinson’s disease familial mutations α-helical structure Molecules Molecules 1420-3049 MDPI