title: Structural and functional properties of prefibrillar α-synuclein oligomers.
abstract: The deposition of fibrillar alpha-synuclein (α-syn) within inclusions (Lewy bodies and Lewy neurites) in neurons and glial cells is a hallmark of synucleinopathies. α-syn populates a variety of assemblies ranging from prefibrillar oligomeric species to fibrils whose specific contribution to neurodegeneration is still unclear. Here, we compare the specific structural and biological properties of distinct soluble prefibrillar α-syn oligomers formed either spontaneously or in the presence of dopamine and glutaraldehyde. We show that both on-fibrillar assembly pathway and distinct dopamine-mediated and glutaraldehyde-cross-linked α-syn oligomers are only slightly effective in perturbing cell membrane integrity and inducing cytotoxicity, while mature fibrils exhibit the highest toxicity. In contrast to low-molecular weight and unstable oligomers, large stable α-syn oligomers seed the aggregation of soluble α-syn within reporter cells although to a lesser extent than mature α-syn fibrils. These oligomers appear elongated in shape. Our findings suggest that α-syn oligomers represent a continuum of species ranging from unstable low molecular weight particles to mature fibrils via stable elongated oligomers composed of more than 15 α-syn monomers that possess seeding capacity.
authors.affiliation: Paris-Saclay Institute of Neuroscience, Centre National de la Recherche Scientifique, Université Paris-Saclay, 91190 Gif-sur-Yvette, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Pieri
authors.affiliation: Paris-Saclay Institute of Neuroscience, Centre National de la Recherche Scientifique, Université Paris-Saclay, 91190 Gif-sur-Yvette, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Madiona
authors.affiliation: Paris-Saclay Institute of Neuroscience, Centre National de la Recherche Scientifique, Université Paris-Saclay, 91190 Gif-sur-Yvette, France.
authors.forename: Ronald
authors.initials: R
authors.lastname: Melki
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival; D006801:Humans; D046911:Macromolecular Substances / Q000378:metabolism* / Q000633:toxicity* / Q000648:ultrastructure; D008853:Microscopy; D009474:Neurons / Q000502:physiology; D011487:Protein Conformation; D055503:Protein Multimerization; D051844:alpha-Synuclein / Q000378:metabolism* / Q000633:toxicity* / Q000648:ultrastructure
chemical_list: D046911:Macromolecular Substances; D051844:alpha-Synuclein