Structural basis of membrane disruption and cellular toxicity by α‑synuclein oligomers
Structural basis of membrane disruption and cellular toxicity by α‑synuclein oligomers
Oligomeric species populated during the aggregation process of α-synuclein have been linked to neuronal impairment in Parkinson’s disease and related neurodegenerative disorders. By using solution and solid-state nuclear magnetic resonance techniques in conjunction with other structural methods, we identified the fundamental characteristics that enable toxic α-synuclein oligomers to perturb biological membranes and disrupt cellular function; these include a highly lipophilic element that promotes strong membrane interactions and a structured region that inserts into lipid bilayers and disrupts their integrity. In support of these conclusions, mutations that target the region that promotes strong membrane interactions by α-synuclein oligomers suppressed their toxicity in neuroblastoma cells and primary cortical neurons.
1440-1443
Fusco, Giuliana
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Chen, Serene W.
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Williamson, Philip T.
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Cascella, Roberta
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Perni, Michele
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Jarvis, James A.
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Cecchi, Cristina
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Vendruscolo, Michele
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Chiti, Fabrizio
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Cremades, Nunilo
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Ying, Liming
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Dobson, Christopher M.
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De Simone, Alfonso
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15 December 2017
Fusco, Giuliana
ca4cea04-719c-42e8-b549-061d1d4835c0
Chen, Serene W.
ac405529-3375-471a-8257-bda5c0d10e53
Williamson, Philip T.
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Cascella, Roberta
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Perni, Michele
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Jarvis, James A.
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Cecchi, Cristina
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Vendruscolo, Michele
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Chiti, Fabrizio
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Cremades, Nunilo
a803e387-3830-427d-8774-6bf31c2e289c
Ying, Liming
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Dobson, Christopher M.
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De Simone, Alfonso
ac3d9b86-fb3a-49ce-a316-c09643f5bb50
Fusco, Giuliana, Chen, Serene W., Williamson, Philip T., Cascella, Roberta, Perni, Michele, Jarvis, James A., Cecchi, Cristina, Vendruscolo, Michele, Chiti, Fabrizio, Cremades, Nunilo, Ying, Liming, Dobson, Christopher M. and De Simone, Alfonso
(2017)
Structural basis of membrane disruption and cellular toxicity by α‑synuclein oligomers.
Science, 358 (6369), .
(doi:10.1126/science.aan6160).
Abstract
Oligomeric species populated during the aggregation process of α-synuclein have been linked to neuronal impairment in Parkinson’s disease and related neurodegenerative disorders. By using solution and solid-state nuclear magnetic resonance techniques in conjunction with other structural methods, we identified the fundamental characteristics that enable toxic α-synuclein oligomers to perturb biological membranes and disrupt cellular function; these include a highly lipophilic element that promotes strong membrane interactions and a structured region that inserts into lipid bilayers and disrupts their integrity. In support of these conclusions, mutations that target the region that promotes strong membrane interactions by α-synuclein oligomers suppressed their toxicity in neuroblastoma cells and primary cortical neurons.
Text
Science_Report_03_11_17_1_
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More information
Accepted/In Press date: 14 November 2017
e-pub ahead of print date: 15 December 2017
Published date: 15 December 2017
Identifiers
Local EPrints ID: 416637
URI: http://eprints.soton.ac.uk/id/eprint/416637
ISSN: 0036-8075
PURE UUID: 88d64f3e-7d3b-4bc7-aa32-b989ffb2c2d9
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Date deposited: 03 Jan 2018 17:31
Last modified: 16 Mar 2024 05:56
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Contributors
Author:
Giuliana Fusco
Author:
Serene W. Chen
Author:
Roberta Cascella
Author:
Michele Perni
Author:
James A. Jarvis
Author:
Cristina Cecchi
Author:
Michele Vendruscolo
Author:
Fabrizio Chiti
Author:
Nunilo Cremades
Author:
Liming Ying
Author:
Christopher M. Dobson
Author:
Alfonso De Simone
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