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

doi:10.1021/jacs.4c02262

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 newspaper › Journal article › Research › peer-review

7 Citations (Scopus)

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 language	English
Journal	Journal of the American Chemical Society
Volume	146
Issue	18
Pages (from-to)	12702-12711
Number of pages	10
ISSN	0002-7863
DOIs	https://doi.org/10.1021/jacs.4c02262
Publication status	Published - May 2024

Keywords

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

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Santos, J., Cuellar, J., Pallarès, 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. E., & Ventura, S. (2024). A Targetable N-Terminal Motif Orchestrates α-Synuclein Oligomer-to-Fibril Conversion. Journal of the American Chemical Society, 146(18), 12702-12711. https://doi.org/10.1021/jacs.4c02262

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title = "A Targetable N-Terminal Motif Orchestrates α-Synuclein Oligomer-to-Fibril Conversion",

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.",

keywords = "alpha-Synuclein/chemistry, Humans, Parkinson Disease/metabolism, Amino Acid Motifs",

author = "Jaime Santos and Jorge Cuellar and Irantzu Pallar{\`e}s and Byrd, {Emily J} and Alons Lends and Fernando Moro and Abdul-Shukkoor, {Muhammed Bilal} and Jordi Pujols and Lorea Velasco-Carneros and Frank Sobott and Otzen, {Daniel E} and Calabrese, {Antonio N} and Arturo Muga and Pedersen, {Jan Skov} and Antoine Loquet and Valpuesta, {Jose Mar{\'i}a} and Radford, {Sheena E} and Salvador Ventura",

year = "2024",

month = may,

doi = "10.1021/jacs.4c02262",

language = "English",

volume = "146",

pages = "12702--12711",

journal = "Journal of the American Chemical Society",

issn = "0002-7863",

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Santos, J, Cuellar, J, Pallarès, I, Byrd, EJ, Lends, A, Moro, F, Abdul-Shukkoor, MB, Pujols, J, Velasco-Carneros, L, Sobott, F, Otzen, DE, Calabrese, AN, Muga, A, Pedersen, JS, Loquet, A, Valpuesta, JM, Radford, SE & Ventura, S 2024, 'A Targetable N-Terminal Motif Orchestrates α-Synuclein Oligomer-to-Fibril Conversion', Journal of the American Chemical Society, vol. 146, no. 18, pp. 12702-12711. https://doi.org/10.1021/jacs.4c02262

A Targetable N-Terminal Motif Orchestrates α-Synuclein Oligomer-to-Fibril Conversion. / Santos, Jaime; Cuellar, Jorge; Pallarès, Irantzu et al.
In: Journal of the American Chemical Society, Vol. 146, No. 18, 05.2024, p. 12702-12711.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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T1 - A Targetable N-Terminal Motif Orchestrates α-Synuclein Oligomer-to-Fibril Conversion

AU - Santos, Jaime

AU - Cuellar, Jorge

AU - Pallarès, Irantzu

AU - Byrd, Emily J

AU - Lends, Alons

AU - Moro, Fernando

AU - Abdul-Shukkoor, Muhammed Bilal

AU - Pujols, Jordi

AU - Velasco-Carneros, Lorea

AU - Sobott, Frank

AU - Otzen, Daniel E

AU - Calabrese, Antonio N

AU - Muga, Arturo

AU - Pedersen, Jan Skov

AU - Loquet, Antoine

AU - Valpuesta, Jose María

AU - Radford, Sheena E

AU - Ventura, Salvador

PY - 2024/5

Y1 - 2024/5

N2 - 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.

AB - 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.

KW - alpha-Synuclein/chemistry

KW - Humans

KW - Parkinson Disease/metabolism

KW - Amino Acid Motifs

UR - http://www.scopus.com/inward/record.url?scp=85192058292&partnerID=8YFLogxK

U2 - 10.1021/jacs.4c02262

DO - 10.1021/jacs.4c02262

M3 - Journal article

C2 - 38683963

SN - 0002-7863

VL - 146

SP - 12702

EP - 12711

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

IS - 18

ER -

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

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