The cassette exons of α-synuclein play distinct roles in membrane remodelling and membrane-mediated amyloid formation
- 1Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Health and Life Sciences, University of Leeds Leeds LS2 9JT UK.
Abstract
Membranes are central to both the physiological and pathological roles of α-synuclein (αSyn). Here, we define the roles of exons 3 and 5 of αSyn in membrane interactions and determine how alternative splicing influences membrane binding, protein conformation, membrane remodelling and lipid-induced amyloid formation. We show that deletion of residues encoded by exon 3 reduces membrane-bound helicity to a greater extent than expected from the loss of those residues alone, diminishes the ability of αSyn to lower the membrane gel-to-fluid transition temperature (T m), and shifts membrane remodelling behaviour from tubulation to fission. Conversely, deletion of exon 5-encoded residues has little effect on membrane affinity, membrane-induced helix formation, modulation of liposomal T m, or membrane remodelling activity. Despite this, deletions of these residues play a key role in determining the flux through different pathways for lipid-induced amyloid formation, resulting in the formation of structurally distinct fibril populations. Thus, exons 3 and 5 make mechanistically distinct contributions to the relationship between αSyn and membranes with different effects on protein conformation and aggregation. Together, these findings demonstrate that alternative splicing remodels the interplay between αSyn, membranes, and amyloid formation. Mapping the sequence determinants that underlie these processes provides insight into how alternative splicing changes both the physiological functions of αSyn and its involvement in disease.
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BibTeX
@article{dewison2026cassette,
title = {{The cassette exons of α-synuclein play distinct roles in membrane remodelling and membrane-mediated amyloid formation}},
author = {Katherine M Dewison and Pijush Chakraborty and David J Brockwell and Sheena E Radford},
journal = {Chemical science},
year = {2026},
month = nov,
doi = {10.1039/d6sc07425a},
url = {https://europepmc.org/article/PMC/PMC13726718},
note = {CC BY},
}
RIS
TY - JOUR
TI - The cassette exons of α-synuclein play distinct roles in membrane remodelling and membrane-mediated amyloid formation
AU - Katherine M Dewison
AU - Pijush Chakraborty
AU - David J Brockwell
AU - Sheena E Radford
PY - 2026
DA - 2026/11/02
JO - Chemical science
DO - 10.1039/d6sc07425a
UR - https://europepmc.org/article/PMC/PMC13726718
AB - Membranes are central to both the physiological and pathological roles of α-synuclein (αSyn). Here, we define the roles of exons 3 and 5 of αSyn in membrane interactions and determine how alternative splicing influences membrane binding, protein conformation, membrane remodelling and lipid-induced amyloid formation. We show that deletion of residues encoded by exon 3 reduces membrane-bound helicity to a greater extent than expected from the loss of those residues alone, diminishes the ability of αSyn to lower the membrane gel-to-fluid transition temperature (T m), and shifts membrane remodelling behaviour from tubulation to fission. Conversely, deletion of exon 5-encoded residues has little effect on membrane affinity, membrane-induced helix formation, modulation of liposomal T m, or membrane remodelling activity. Despite this, deletions of these residues play a key role in determining the flux through different pathways for lipid-induced amyloid formation, resulting in the formation of structurally distinct fibril populations. Thus, exons 3 and 5 make mechanistically distinct contributions to the relationship between αSyn and membranes with different effects on protein conformation and aggregation. Together, these findings demonstrate that alternative splicing remodels the interplay between αSyn, membranes, and amyloid formation. Mapping the sequence determinants that underlie these processes provides insight into how alternative splicing changes both the physiological functions of αSyn and its involvement in disease.
SN - 2041-6520
SN - 2041-6539
ER -