Developmental Biology & Disease Mechanisms
Erythrocyte (patho)physiology and storage in transfusion units
In contrast to long-held views, erythrocytes are not merely bags full of hemoglobin but equipped with a large set of signaling components, currently emerging as important players in various physiologic processes. We, Ernst Müllner and Ulrich Salzer, teamed up with clinical cooperators from Vienna, Munich and Dresden to explore the intricate regulatory properties, diagnostic potential and therapeutic possibilities/limitations of these most abundant...more
In contrast to long-held views, erythrocytes are not merely bags full of hemoglobin but equipped with a large set of signaling components, currently emerging as important players in various physiologic processes. We, Ernst Müllner and Ulrich Salzer, teamed up with clinical cooperators from Vienna, Munich and Dresden to explore the intricate regulatory properties, diagnostic potential and therapeutic possibilities/limitations of these most abundant blood cells.
Basic research on erythrocyte physiology
· Erythrocytes actively engage in blood clotting and thrombus formation. Lysophosphatidic acid (LPA) from activated platelets triggers rapid exposure of phophatidylserine (PS) at the cell surface, resulting in an amplification of the clotting cascade. We currently explore the intracellular signaling and the molecular players of this process.
· Due to their function as oxygen carriers, erythrocytes are loaded with an arsenal of molecules preventing oxidative stress. In an ongoing project, we study the complex regulation of the response to intracellular oxidative stress and the involvement of erythrocytes in the defense against oxidative stressors in blood plasma.
Research on erythrocytes to identify molecular mechanisms underlying neurodegeneration
The rare congenital neurodegenerative disorders chorea acanthocytosis (ChAC), McLeod syndrome and pantothenate kinase-associated neurodegeneration(PKAN) are classified as neuroacanthocytoses (NA)due to the occurrence of mis-shaped erythrocytes aka acanthoytes. We found that LPA signaling is deregulated in NA erythrocytes resulting in aberrant PS exposure and calcium uptake. Moreover, we found that drug-induced endovesiculation is impaired in NA erythrocytes (Siegl et al, 2013).
· A current study on ChAc erythrocytes indicates that the altered endovesiculation properties are due to reduced dynamics and reversibility in the interaction between plasma membrane and cytoskeleton (Figure 1).
· PKAN is often caused by point mutations in the PANK2 gene (Schiessl-Weyer et al, 2015). We use erythrocytes from PKAN patients to assess stability and activity of Pank2 mutants and study the impact on coenzyme A level and regulatory properties within these cells.
Assessing the quality of erythrocytes in transfusion units
Blood transfusion is routinely applied in many clinical settings. Apart from blood typing and a storage time limit of 42 days, however, standards regarding quality of transfusion units are still lacking. We investigate molecular changes that occur during the storage of transfusion units. This aims at the assessment of inter-donor and -recipient variability and at the identification of novel molecular markers indicating the degree of senescence within stored erythrocytes.
Kostan J, Salzer U, Orlova A, Toeroe I, Hodnik V, Senju Y, Zou J, Schreiner C, Steiner J, Meriläinen J, Nikki M, Virtanen I, Carugo O, Rappsilber J, Lappalainen P, Lehto VP, Anderluh G, Egelman EH, Djinović-Carugo K (2014). Direct Interaction of Actin Filaments with F-BAR Protein Pacsin2. EMBO REP;15(11):1154-62. PMID: 25216944
Schiessl-Weyer, Jasmin; Roa, Pedro; Laccone, Franco; Kluge, Britta; Tichy, Alexander; De Almeida Ribeiro, Euripedes; Prohaska, Rainer; Stoeter, Peter; Siegl, Claudia; Salzer, Ulrich (2015). Acanthocytosis and the c.680 A>G Mutation in the PANK2 Gene: A Study Enrolling a Cohort of PKAN Patients from the Dominican Republic. PLOS ONE;10(4):e0125861. PMID: 25915509
Siegl, Claudia; Hamminger, Patricia; Jank, Herbert; Ahting, Uwe; Bader, Benedikt; Danek, Adrian; Gregory, Allison; Hartig, Monika; Hayflick, Susan; Hermann, Andreas; Prokisch, Holger; Sammler, Esther M; Yapici, Zuhal; Prohaska, Rainer; Salzer, Ulrich (2013). Alterations of red cell membrane properties in nneuroacanthocytosis. PLOS ONE;8(10):e76715. PMID: 24098554