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Tipping point in α-synuclein-membrane interactions from stable protein-covered vesicles to amyloid aggregation

Makasewicz, Katarzyna LU ; Carlström, Göran LU orcid ; Stenström, Olof LU ; Bernfur, Katja LU ; Fridolf, Simon LU ; Akke, Mikael LU orcid ; Linse, Sara LU and Sparr, Emma LU (2024) In Cell Reports Physical Science 5(12).
Abstract

α-synuclein is a neuronal protein implicated in neurotransmitter release. Its function is thought to critically depend on the dynamic equilibrium between its free and its membrane-bound state. α-synuclein amyloid formation, implicated in Parkinson's disease, is also modulated by lipid membranes. The interplay between these processes remains elusive yet relates to the outstanding question of what determines the switch between physiological and disease-related behavior of the protein. Here, we study the coupling of equilibrium between free and membrane-bound α-synuclein and membrane-induced amyloid formation at lipid-to-protein ratios where amyloid formation is either accelerated or inhibited by lipid membranes. We find a clear difference... (More)

α-synuclein is a neuronal protein implicated in neurotransmitter release. Its function is thought to critically depend on the dynamic equilibrium between its free and its membrane-bound state. α-synuclein amyloid formation, implicated in Parkinson's disease, is also modulated by lipid membranes. The interplay between these processes remains elusive yet relates to the outstanding question of what determines the switch between physiological and disease-related behavior of the protein. Here, we study the coupling of equilibrium between free and membrane-bound α-synuclein and membrane-induced amyloid formation at lipid-to-protein ratios where amyloid formation is either accelerated or inhibited by lipid membranes. We find a clear difference between the exchange dynamics and the heterogeneity of the protein-covered membrane interface under these two sets of conditions. Our results highlight a strong coupling of membrane-modulated amyloid formation and the equilibrium between free and membrane-bound α-synuclein, which advances our molecular understanding of the physiological function of α-synuclein and its aberrant aggregation.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
amyloid formation, exchange dynamics, HSQC NMR, lipid membranes, PFG diffusion NMR, protein corona, protein-lipid co-aggregation, protein-membrane interactions, α-synuclein
in
Cell Reports Physical Science
volume
5
issue
12
article number
102309
publisher
Cell Press
external identifiers
  • scopus:85212349235
ISSN
2666-3864
DOI
10.1016/j.xcrp.2024.102309
language
English
LU publication?
yes
id
04ecfa70-b985-441a-a4b8-c34089551ca0
date added to LUP
2025-01-20 11:11:53
date last changed
2025-04-04 14:24:39
@article{04ecfa70-b985-441a-a4b8-c34089551ca0,
  abstract     = {{<p>α-synuclein is a neuronal protein implicated in neurotransmitter release. Its function is thought to critically depend on the dynamic equilibrium between its free and its membrane-bound state. α-synuclein amyloid formation, implicated in Parkinson's disease, is also modulated by lipid membranes. The interplay between these processes remains elusive yet relates to the outstanding question of what determines the switch between physiological and disease-related behavior of the protein. Here, we study the coupling of equilibrium between free and membrane-bound α-synuclein and membrane-induced amyloid formation at lipid-to-protein ratios where amyloid formation is either accelerated or inhibited by lipid membranes. We find a clear difference between the exchange dynamics and the heterogeneity of the protein-covered membrane interface under these two sets of conditions. Our results highlight a strong coupling of membrane-modulated amyloid formation and the equilibrium between free and membrane-bound α-synuclein, which advances our molecular understanding of the physiological function of α-synuclein and its aberrant aggregation.</p>}},
  author       = {{Makasewicz, Katarzyna and Carlström, Göran and Stenström, Olof and Bernfur, Katja and Fridolf, Simon and Akke, Mikael and Linse, Sara and Sparr, Emma}},
  issn         = {{2666-3864}},
  keywords     = {{amyloid formation; exchange dynamics; HSQC NMR; lipid membranes; PFG diffusion NMR; protein corona; protein-lipid co-aggregation; protein-membrane interactions; α-synuclein}},
  language     = {{eng}},
  number       = {{12}},
  publisher    = {{Cell Press}},
  series       = {{Cell Reports Physical Science}},
  title        = {{Tipping point in α-synuclein-membrane interactions from stable protein-covered vesicles to amyloid aggregation}},
  url          = {{http://dx.doi.org/10.1016/j.xcrp.2024.102309}},
  doi          = {{10.1016/j.xcrp.2024.102309}},
  volume       = {{5}},
  year         = {{2024}},
}