To understand and treat the molecular causes of premature red blood cell aging in thalassemia patients

Beta-thalassemia is a common inherited hemoglobinopathy that is characterized by impaired or absent beta-globin chain production and subsequent accumulation of unpaired alpha-globin subunits. Alpha-globin chains aggregation and precipitation is a central feature of beta-thalassemia physiopathology, causing ineffective erythropoiesis, and premature RBC aging causing hemolysis and anemia.

While ineffective erythropoiesis has been the subject of intense research for many years, improving the circulation quality of mature RBCs remains poorly investigated. Thanks to our knowledge on the specific aging process occurring in these highly differentiated cells, we aim to decipher the molecular causes leading to premature aging of thalassemic RBCs, with the long-term goal to improve thalassemic patients’ care. Indeed, RBCs are not sensitive to most of the common age-related alterations observed in nucleated cells since they are devoid of organelles such as the nucleus and lysosomes. In addition, since they no longer have the capacity to synthesize new proteins, misfolded/oxidized proteins that accumulate must be repaired, destroyed or eliminated to avoid the formation of toxic aggregates. Protein homeostasis (proteostasis) dysfunction thus appears as the main, and possibly the only, hallmark of aging shared by RBCs with nucleated cells.

To this end, we will test our overarching hypothesis that: the ability to resist the decline of proteostasis function determines the thalassemic RBC circulation quality. We propose that RBC integrity is maintained by its capacity to refold misfolded proteins using chaperones and to degrade damaged/oxidized proteins by the proteasome, avoiding the formation of (membrane-bound) toxic aggregates. Cellular and molecular markers of in vivo aging will be characterized regularly during the RBC lifespan. Particular attention will be paid to tandem mass tag-based quantitative proteomics and post-translational modifications (oxidations, ubiquitination) linked to proteostasis activity.

Selected publications

Peltier S, Marin M, Dzieciatkowska M, Dussiot M, Roy MK, Bruce J, Leblanc L, Hadjou Y, Georgeault S, Fricot A, Roussel C, Stephenson D, Casimir M, Sissoko A, Paye F, Dokmak S, Ndour PA, Roingeard P, Gautier EF, Spitalnik SL, Hermine O, Buffet PA, D'Alessandro A, Amireault P.

Proteostasis and metabolic dysfunction characterize a subset of storage-induced senescent erythrocytes targeted for posttransfusion clearance.

J Clin Invest. 2025 https://pubmed.ncbi.nlm.nih.gov/40067362/

Casimir M, Colard M, Dussiot M, Roussel C, Martinez A, Peyssonnaux C, Mayeux P, Benghiat S, Manceau S, Francois A, Marin N, Pène F, Buffet PA, Hermine O, Amireault P.

Erythropoietin downregulates red blood cell clearance, increasing transfusion efficacy in severely anemic recipients.

Am J Hematol. 2023 https://pubmed.ncbi.nlm.nih.gov/37792521/

Roussel C, Morel A, Dussiot M, Marin M, Colard M, Fricot-Monsinjon A, Martinez A, Chambrion C, Henry B, Casimir M, Volle G, Dépond M, Dokmak S, Paye F, Sauvanet A, Le Van Kim C, Colin Y, Georgeault S, Roingeard P, Spitalnik SL, Ndour PA, Hermine O, Hod EA, Buffet PA, Amireault P.

Rapid clearance of storage-induced microerythrocytes alters transfusion recovery.

Blood. 2021 https://pubmed.ncbi.nlm.nih.gov/33657208/