Monomers, Dimers, and Oligomers of Pyroglutamate-Modified α-Synuclein Fragments Exhibit Distinct Biophysical Characteristics
Bluhm A, Xiang W, Wien F, Thureau A, Chevreuil M, Raynal B, Geissler S, Wermann M, Schilling S, Bénas P, Hartlage-Rübsamen M, Schulze A, Sauter C, Roßner S (2025)
Publication Type: Journal article
Publication year: 2025
Journal
DOI: 10.1021/acschemneuro.5c00106
Abstract
α-Synuclein (aSyn) aggregation represents a key event in the neurodegenerative cascade of synucleinopathies. Initially, aSyn appears as an intrinsically disordered protein. However, its structural flexibility allows aSyn to either adopt α-helical conformations, relevant for physiological functions at presynaptic vesicles, or form β-strand-rich aggregates, leading to toxic oligomers. This relation between structure, function, and toxicity can be influenced by post-translational modifications such as the recently identified glutaminyl cyclase-catalyzed pyroglutamate (pE) modification. Here, we investigated (i) structural characteristics of monomeric, dimeric, and oligomeric states of N-terminal truncated, pE-modified aSyn variants, pE24-, pE62-, and pE79-aSyn by a complementary biophysical approach including DLS, SEC-MALS, SRCD, SEC-SAXS, and AUC and (ii) the toxicity of oligomeric pE-aSyn variants compared to full-length aSyn. Overall, pE62-aSyn showed an immediate fibril formation, reflecting the aggregation-prone properties of this particular variant. Furthermore, in a membrane-like environment, the secondary aSyn structure shifted toward α-helical folding depending on the degree of N-terminal truncation. pE79-aSyn showed a significantly reduced level of structural adaptation, reflecting compromised functions at presynaptic vesicles. In addition, the comparative analysis indicates the presence of a dimeric aSyn intermediate, the initial and potentially crucial step in aSyn aggregation, and supports the hypothesis of a toxic porous oligomeric state. For the first time, based on SAXS data, EOM models of the dimeric aSyn state are proposed.
Authors with CRIS profile
Involved external institutions
Universität Leipzig
Germany (DE)
Synchrotron SOLEIL
France (FR)
Université Sorbonne Paris Cité
France (FR)
Fraunhofer-Institut für Zelltherapie und Immunologie (IZI)
Germany (DE)
Architecture et Réactivité de l'arN
France (FR)
Germany (DE)
Synchrotron SOLEIL
France (FR)
Université Sorbonne Paris Cité
France (FR)
Fraunhofer-Institut für Zelltherapie und Immunologie (IZI)
Germany (DE)
Architecture et Réactivité de l'arN
France (FR)
How to cite
APA:
Bluhm, A., Xiang, W., Wien, F., Thureau, A., Chevreuil, M., Raynal, B.,... Roßner, S. (2025). Monomers, Dimers, and Oligomers of Pyroglutamate-Modified α-Synuclein Fragments Exhibit Distinct Biophysical Characteristics. ACS Chemical Neuroscience. https://doi.org/10.1021/acschemneuro.5c00106
MLA:
Bluhm, Alexandra, et al. "Monomers, Dimers, and Oligomers of Pyroglutamate-Modified α-Synuclein Fragments Exhibit Distinct Biophysical Characteristics." ACS Chemical Neuroscience (2025).
BibTeX: Download