The structural architecture of an α-synuclein toxic oligomer

Santos, J.; Cuellar, J.; Pallares, I.; Byrd, E. J.; Lends, A.; Moro, F.; Abdul-Shukkoor, M. B.; Pujols, J.; Velasco-Carneros, L.; Sobott, F.; Otzen, D. E.; Calabrese, A. N.; Muga, A.; Pedersen, J. S.; Loquet, A.; Valpuesta, J. M.; Radford, S.; Ventura, S.

doi:10.1101/2023.02.10.527650

bioRxiv · 10.1101/2023.02.10.527650

The structural architecture of an α-synuclein toxic oligomer

Santos, J.·Cuellar, J.·Pallares, I.·Byrd, E. J.·Lends, A.·Moro, F.·Abdul-Shukkoor, M. B.·Pujols, J.·Velasco-Carneros, L.·Sobott, F.·Otzen, D. E.·Calabrese, A. N.·Muga, A.·Pedersen, J. S.·Loquet, A.·Valpuesta, J. M.·Radford, S.·Ventura, S.

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Abstract

Oligomeric species populated during -synuclein aggregation are considered key drivers of neurodegeneration in Parkinsons disease. However, the development of oligomer-targeting therapeutics is constrained by our limited knowledge of their structure and the molecular determinants driving their conversion to fibrils. PSM3 is a nanomolar peptide binder of -synuclein oligomers that inhibits aggregation by blocking oligomer to fibril conversion. Here, we investigate the binding of PSM3 to -synuclein oligomers to discover the mechanistic basis of this protective activity. We find that PSM3 selectively targets an -synuclein N-terminal motif (residues 36-61) that populates a distinct conformation in the monomeric and oligomeric states. This -synuclein region plays a pivotal role in oligomer to fibril conversion, as its absence renders the central NAC domain insufficient to prompt this structural transition. The hereditary mutation G51D, associated with early-onset Parkinsons disease, causes a conformational fluctuation in this region, leading to delayed oligomer to fibril conversion and an accumulation of oligomers that are resistant to remodeling by molecular chaperones. Overall, our findings unveil a new targetable region in -synuclein oligomers, advance our comprehension of oligomer to amyloid fibril conversion and reveal a new facet of -synuclein pathogenic mutations.

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Santos, J., Cuellar, J., Pallares, I., Byrd, E. J., Lends, A., Moro, F., Abdul-Shukkoor, M. B., Pujols, J., Velasco-Carneros, L., Sobott, F., Otzen, D. E., Calabrese, A. N., Muga, A., Pedersen, J. S., Loquet, A., Valpuesta, J. M., Radford, S., Ventura, S.. 2023-02-10. The structural architecture of an α-synuclein toxic oligomer. https://doi.org/10.1101/2023.02.10.527650

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