A Targetable N-Terminal Motif Orchestrates α-Synuclein Oligomer-to-Fibril Conversion

Jaime Santos, Jorge Cuellar, Irantzu Pallarès, Emily J Byrd, Alons Lends, Fernando Moro, Muhammed Bilal Abdul-Shukkoor, Jordi Pujols, Lorea Velasco-Carneros, Frank Sobott, Daniel E Otzen, Antonio N Calabrese, Arturo Muga, Jan Skov Pedersen, Antoine Loquet, Jose María Valpuesta, Sheena E Radford, Salvador Ventura*

*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Abstract

Oligomeric species populated during α-synuclein aggregation are considered key drivers of neurodegeneration in Parkinson's 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. Phenol-soluble modulin α3 (PSMα3) is a nanomolar peptide binder of α-synuclein oligomers that inhibits aggregation by blocking oligomer-to-fibril conversion. Here, we investigate the binding of PSMα3 to α-synuclein oligomers to discover the mechanistic basis of this protective activity. We find that PSMα3 selectively targets an α-synuclein N-terminal motif (residues 36-61) that populates a distinct conformation in the mono- and oligomeric states. This α-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 Parkinson's 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 α-synuclein oligomers, advance our comprehension of oligomer-to-amyloid fibril conversion, and reveal a new facet of α-synuclein pathogenic mutations.

Original languageEnglish
JournalJournal of the American Chemical Society
Volume146
Issue18
Pages (from-to)12702-12711
Number of pages10
ISSN0002-7863
DOIs
Publication statusPublished - May 2024

Keywords

  • alpha-Synuclein/chemistry
  • Humans
  • Parkinson Disease/metabolism
  • Amino Acid Motifs

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