Leri, M;
Bemporad, F;
Oropesa-Nunez, R;
Canale, C;
Calamai, M;
Nosi, D;
Ramazzotti, M;
... Bucciantini, M; + view all
(2016)
Molecular insights into cell toxicity of a novel familial amyloidogenic variant of beta 2-microglobulin.
Journal of Cellular and Molecular Medicine
, 20
(8)
pp. 1443-1456.
10.1111/jcmm.12833.
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Abstract
The first genetic variant of β2-microglobulin (b2M) associated with a familial form of systemic amyloidosis has been recently described. The mutated protein, carrying a substitution of Asp at position 76 with an Asn (D76N b2M), exhibits a strongly enhanced amyloidogenic tendency to aggregate with respect to the wild-type protein. In this study, we characterized the D76N b2M aggregation path and performed an unprecedented analysis of the biochemical mechanisms underlying aggregate cytotoxicity. We showed that, contrarily to what expected from other amyloid studies, early aggregates of the mutant are not the most toxic species, despite their higher surface hydrophobicity. By modulating ganglioside GM1 content in cell membrane or synthetic lipid bilayers, we confirmed the pivotal role of this lipid as aggregate recruiter favouring their cytotoxicity. We finally observed that the aggregates bind to the cell membrane inducing an alteration of its elasticity (with possible functional unbalance and cytotoxicity) in GM1-enriched domains only, thus establishing a link between aggregate-membrane contact and cell damage.
| Type: | Article |
|---|---|
| Title: | Molecular insights into cell toxicity of a novel familial amyloidogenic variant of beta 2-microglobulin |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1111/jcmm.12833 |
| Publisher version: | http://dx.doi.org/10.1111/jcmm.12833 |
| Language: | English |
| Additional information: | © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Cell Biology, Medicine, Research & Experimental, Research & Experimental Medicine, Membrane Bilayers, Amyloid Cytotoxicity, Gm1 Ganglioside, Protein Misfolding, Systemic Amyloidosis, Neutral Ph, Protein Oligomers, Gm1 Ganglioside, Beta-Peptide, Lipid Rafts, Membranes, Fibrils, Beta(2)-Microglobulin, Association, Dynamics |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1531025 |
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