Molecular insights into cell toxicity of a novel familial amyloidogenic variant of β2‐microglobulin. Issue 8 (18th March 2016)

• Record Type: Journal Article
• Authors: Leri, Manuela; Bemporad, Francesco; Oropesa‐Nuñez, Reinier; Canale, Claudio; Calamai, Martino; Nosi, Daniele; Ramazzotti, Matteo; Giorgetti, Sofia; Pavone, Francesco S.; Bellotti, Vittorio; Stefani, Massimo; Bucciantini, Monica
• Is Part Of: Journal of cellular and molecular medicine. Volume 20:Issue 8(2016)
• Page Start: 1443
• Page End: 1456
• Publication Date: 2016-03-18
• Subjects: membrane bilayers -- amyloid cytotoxicity -- GM1 ganglioside -- protein misfolding -- systemic amyloidosis; Cytology; Medicine; Molecular Biology; Cytologie -- Périodiques; Médecine -- Périodiques; Biologie moléculaire -- Périodiques; Cytology -- Periodicals; Medicine -- Periodicals; Molecular biology -- Periodicals; 611.01805
• DOI: 10.1111/jcmm.12833
• Languages: English
• ISSNs: 1582-1838

Abstract

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.