Molecular insights into cell toxicity of a novel familial amyloidogenic variant of β2-microglobulin
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Published on: September 28, 2019
Manuela Leri1, Francesco Bemporad1, Reinier Oropesa-Nuñez2
1Dipartimento di Scienze Biomediche, Sperimentali e Cliniche 'Mario Serio', Università degli Studi di Firenze, Firenze, Italy.
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.
Insights
A new beta2-microglobulin (b2M) variant (D76N b2M) causes familial amyloidosis. Its aggregates damage cell membranes by recruiting ganglioside GM1, altering elasticity and causing cytotoxicity.
Area of Science:
- Biochemistry
- Cell Biology
- Genetics
Background:
- A novel genetic variant of beta2-microglobulin (b2M), D76N b2M, is linked to familial systemic amyloidosis.
- This mutation significantly increases the protein's tendency to aggregate compared to wild-type b2M.
Purpose of the Study:
- To investigate the aggregation pathway of D76N b2M.
- To analyze the biochemical mechanisms responsible for the cytotoxicity of D76N b2M aggregates.
- To elucidate the role of ganglioside GM1 in D76N b2M-induced cytotoxicity.
Main Methods:
- Characterization of D76N b2M aggregation.
- Analysis of aggregate cytotoxicity using cell-based assays.
- Modulation of ganglioside GM1 levels in cell membranes and synthetic bilayers.
- Measurement of cell membrane elasticity.
Main Results:
- Early D76N b2M aggregates are not the most toxic species, despite increased surface hydrophobicity.
- Ganglioside GM1 acts as a crucial recruiter of D76N b2M aggregates, enhancing their cytotoxicity.
- D76N b2M aggregates bind to GM1-enriched membrane domains, reducing membrane elasticity and causing cell damage.
Conclusions:
- The cytotoxicity of D76N b2M aggregates is mediated by their interaction with ganglioside GM1 in cell membranes.
- Aggregate-induced alterations in membrane elasticity within GM1 domains are linked to cell damage.
- This study establishes a direct connection between aggregate-membrane interactions and the pathogenesis of D76N b2M amyloidosis.
