Stomatin, membrane microdomains and neuroacanthocytosis
Membrane microdomains or "lipid rafts", lateral complexes of distinct proteins and lipids, are implicated in a variety of functions like signal transduction, vesicle trafficking, sorting of certain proteins and lipids, and cell polarity. We investigate the functions of oligomeric membrane proteins that are typical lipid raft markers, the stomatins and flotillins, particularly in the context of cholesterol trafficking, membrane scaffolding and vesiculation. In a second project, we study red blood cell membrane microdomains in the context of cholesterol availability and associated morphological changes, as presented in the form of acanthocytes in the disease neuroacanthocytosis.
Stomatin is an oligomeric, cholesterol-binding, lipid raft-associated, integral membrane protein that is localized to the cytoplasmic side of the plasma membrane and late endosomes of many cell types. We are studying the structure and function of stomatin focusing on oligomerization, cholesterol-binding, lipid raft-association, and interactions with other membrane proteins, such as the glucose transporter GLUT1. Moreover, we study the role of cholesterol in stomatin-GLUT1 complex formation. For our investigations we are using biochemical, molecular and cell biological methods, complemented by collaborative studies together with partners from the LIMES Institute, Univ. Bonn, the Institute of Biophysics, JKU Linz, and the IGMM, Univ. Montpellier.
European Multidisciplinary Initiative on Neuroacanthocytosis (EMINA)
An ERA-NET/E-RARE network coordinated by Prof. Adrian Danek (LMU, Munich) comprises six partner organizations in Germany, Austria, the Netherlands, France, and Turkey, to take a significant step forward in both basic research and applied clinical research into the neuroacanthocytosis (NA) syndromes. These syndromes are a group of rare neurological illnesses, which affect mostly young adults. NA is associated with neurodegeneration in the brain, similar to Huntington’s Disease, but can be differentiated by the presence of spiky erythrocytes (acanthocytes) in the blood. Several candidate genes for various NA forms have been identified: VPS13A (vacuolar protein sorting 13A) for chorea-acanthocytosis (ChAc), XK (Kell system) for McLeod Syndrome (MLS), JPH3 (junctophilin 3) for Huntington’s Disease-Like 2 (HDL2), and PANK2 (pantothenate kinase 2) for Pantothenate Kinase-Associated Neurodegeneration (PKAN). Our group participates in EMINA basic research by focusing on the identification of acanthocyte membrane domains that differ in composition from the normal, discocyte membrane. We hypothesize that the VPS13A defect will affect vesicle sorting and autophagy in late stage erythropoiesis and thus lead to changes during reticulocyte membrane reorganization. Similar sorting defects may affect autophagy in neurons leading to accumulation of protein aggregates and cell death.
Publications since 2006
Rungaldier, Stefanie; Oberwagner, Walter; Salzer, Ulrich; Csaszar, Edina; Prohaska, Rainer (2013). Stomatin interacts with GLUT1/SLC2A1, band 3/SLC4A1, and aquaporin-1 in human erythrocyte membrane domains. BBA-BIOMEMBRANES;1828(3):956-66. PMID: 23219802
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
Prohaska R, Sibon OC, Rudnicki DD, Danek A, Hayflick SJ, Verhaag EM, Vonk JJ, Margolis RL, Walker RH. (2012). Brain, blood, and iron: Perspectives on the roles of erythrocytes and iron in neurodegeneration. NEUROBIOL DIS;46(3):607-24. PMID: 22426390
Ulrich Salzer, Rainer Prohaska (2011). Flotillin 1 UCSD Nature Molecule Pages.
Ulrich Salzer, Rainer Prohaska (2011). Flotillin 2 UCSD Nature Molecule Pages.
Mairhofer, Mario; Steiner, Marianne; Salzer, Ulrich; Prohaska, Rainer (2009). Stomatin-like protein-1 interacts with stomatin and is targeted to late endosomes. J BIOL CHEM;284(42):29218-29. PMID: 19696025
Montel-Hagen, Amélie; Kinet, Sandrina; Manel, Nicolas; Mongellaz, Cédric; Prohaska, Rainer; Battini, Jean-Luc; Delaunay, Jean; Sitbon, Marc; Taylor, Naomi (2008). [Red cell GLUT1 compensates for the lack of vitamin C synthesis in mammals] M S-MED SCI;24(4):434-6. PMID: 18405646
Montel-Hagen, Amélie; Kinet, Sandrina; Manel, Nicolas; Mongellaz, Cédric; Prohaska, Rainer; Battini, Jean-Luc; Delaunay, Jean; Sitbon, Marc; Taylor, Naomi (2008). Erythrocyte Glut1 triggers dehydroascorbic acid uptake in mammals unable to synthesize vitamin C. CELL;132(6):1039-48. PMID: 18358815
Salzer, Ulrich; Zhu, Rong; Luten, Marleen; Isobe, Hirotaka; Pastushenko, Vassili; Perkmann, Thomas; Hinterdorfer, Peter; Bosman, Giel J C G M (2008). Vesicles generated during storage of red cells are rich in the lipid raft marker stomatin. TRANSFUSION. PMID: 18067507
Paltrinieri, Saverio; Comazzi, Stefano; Ceciliani, Fabrizio; Prohaska, Rainer; Bonfanti, Ugo (2007). Stomatocytosis of Standard Schnauzers is not associated with stomatin deficiency. VET J;173(1):200-3. PMID: 16168686
Salzer, U; Mairhofer, M; Prohaska, R (2007). Stomatin: a new paradigm of membrane organization emerges DYN CELL BIO.
Umlauf, Ellen; Mairhofer, Mario; Prohaska, Rainer (2006). Characterization of the stomatin domain involved in homo-oligomerization and lipid raft association. J BIOL CHEM;281(33):23349-56. PMID: 16766530
Hägerstrand, Henry; Mrówczynska, Lucyna; Salzer, Ulrich; Prohaska, Rainer; Michelsen, Kimmo A; Kralj-Iglic, Veronika; Iglic, Ales (2006). Curvature-dependent lateral distribution of raft markers in the human erythrocyte membrane. MOL MEMBR BIOL;23(3):277-88. PMID: 16785211
Landlinger, Christine; Salzer, Ulrich; Prohaska, Rainer (2006). Myristoylation of human LanC-like protein 2 (LANCL2) is essential for the interaction with the plasma membrane and the increase in cellular sensitivity to adriamycin. Biochimica et biophysica acta.;1758(11):1759-67. PMID: 16979580