A Targetable N-Terminal Motif Orchestrates α-Synuclein Oligomer-to-Fibril Conversion
Santos, Jaime (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Cuellar, Jorge (Centro Nacional de Biotecnología)
Pallarès i Goitiz, Irantzu (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Byrd, Emily (University of Leeds)
Lends, Alons (Université de Bordeaux)
Moro, Fernando (Universidad del País Vasco. Departamento de Bioquímica y Biología Molecular)
Abdul-Shukkoor, Muhammed Bilal (Université de Bordeaux)
Pujols, Jordi (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Velasco-Carneros, Lorea (Universidad del País Vasco. Departamento de Bioquímica y Biología Molecular)
Sobott, Frank (University of Leeds)
Otzen, Daniel E. (Aarhus University)
Calabrese, Antonio N. (University of Leeds)
Muga, Arturo (Universidad del País Vasco. Departamento de Bioquímica y Biología Molecular)
Pedersen, Jan Skov (Aarhus University)
Loquet, Antoine (Université de Bordeaux)
Valpuesta, Jose María (Centro Nacional de Biotecnología)
Radford, Sheena E. (University of Leeds)
Ventura, Salvador (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)

Date:	2024
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.
Grants:	Agencia Estatal de Investigación BIO2017-91475-EXP Agencia Estatal de Investigación PID2022-137963OB-I00 Agencia Estatal de Investigación PID2019-105017RB-I00 Agencia Estatal de Investigación PID2019-111068GB-I00 Ministerio de Ciencia e Innovación FPU17/01157 Agencia Estatal de Investigación PID2019-105872 GB-I00 Agencia Estatal de Investigación PID2022-137175NB-I00
Note:	Altres ajuts: acords transformatius de la UAB
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Published in:	Journal of the American Chemical Society, Vol. 146, Issue 18 (May 2024) , p. 12702−12711, ISSN 1520-5126

DOI: 10.1021/jacs.4c02262
PMID: 38683963

10 p, 10.4 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Biotecnologia i de Biomedicina (IBB)
Articles > Research articles
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