Article

Erythrocyte membrane changes of chorea-acanthocytosis are the result of altered Lyn kinase activity.

Department of Medicine, University of Verona, Piazzale Lo Scuro 10, Verona, Italy.
Blood (Impact Factor: 10.43). 09/2011; 118(20):5652-63. DOI: 10.1182/blood-2011-05-355339
Source: PubMed

ABSTRACT Acanthocytic RBCs are a peculiar diagnostic feature of chorea-acanthocytosis (ChAc), a rare autosomal recessive neurodegenerative disorder. Although recent years have witnessed some progress in the molecular characterization of ChAc, the mechanism(s) responsible for generation of acanthocytes in ChAc is largely unknown. As the membrane protein composition of ChAc RBCs is similar to that of normal RBCs, we evaluated the tyrosine (Tyr)-phosphorylation profile of RBCs using comparative proteomics. Increased Tyr phosphorylation state of several membrane proteins, including band 3, β-spectrin, and adducin, was noted in ChAc RBCs. In particular, band 3 was highly phosphorylated on the Tyr-904 residue, a functional target of Lyn, but not on Tyr-8, a functional target of Syk. In ChAc RBCs, band 3 Tyr phosphorylation by Lyn was independent of the canonical Syk-mediated pathway. The ChAc-associated alterations in RBC membrane protein organization appear to be the result of increased Tyr phosphorylation leading to altered linkage of band 3 to the junctional complexes involved in anchoring the membrane to the cytoskeleton as supported by coimmunoprecipitation of β-adducin with band 3 only in ChAc RBC-membrane treated with the Lyn-inhibitor PP2. We propose this altered association between membrane skeleton and membrane proteins as novel mechanism in the generation of acanthocytes in ChAc.

Download full-text

Full-text

Available from: Giel J C G M Bosman, Jul 03, 2015
1 Follower
 · 
138 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: β -thalassemia is a worldwide distributed monogenic red cell disorder, characterized by the absence or reduced β -globin chain synthesis. Despite the extensive knowledge of the molecular defects causing β -thalassemia, less is known about the mechanisms responsible for the associated ineffective erythropoiesis and reduced red cell survival, which sustain anemia of β -thalassemia. The unbalance of alpha-gamma chain and the presence of pathological free iron promote a severe red cell membrane oxidative stress, which results in abnormal β -thalassemic red cell features. These cells are precociously removed by the macrophage system through two mechanisms: the removal of phosphatidylserine positive cells and through the natural occurring antibody produced against the abnormally clustered membrane protein band 3. In the present review we will discuss the changes in β -thalassemic red cell homeostasis related to the oxidative stress and its connection with production of microparticles and with malaria infection. The reactive oxygen species (ROS) are also involved in ineffective erythropoiesis of β -thalassemia through still partially known pathways. Novel cytoprotective systems such as ASHP, eIF2 α , and peroxiredoxin-2 have been suggested to be important against ROS in β -thalassemic erythropoiesis. Finally, we will discuss the results of the major in vitro and in vivo studies with antioxidants in β -thalassemia.
    Oxidative Medicine and Cellular Longevity 09/2013; 2013:985210. DOI:10.1155/2013/985210 · 3.36 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Band-3 (B3), the anion transporter is an integral membrane protein that plays a key structural role by anchoring the plasma membrane to the spectrin-based membrane skeleton in the red cell. In addition, it also plays a critical role in the assembly of glycolytic enzymes to regulate red cell metabolism. However, its ability to recruit proteins that can prevent membrane oxidation has not been previously explored. In the present study, using a variety of experimental approaches including cross-linking studies, fluorescence and dichroic measurements, surface-plasmon-resonance analysis, and proteolytic digestion assays, we document that the anti-oxidant protein, Peroxiredoxin-2 (PRDX2), the third most abundant cytoplasmic protein in RBCs, interacts with the cytoplasmic domain of B3. The surface electrostatic potential analysis and stoichiometry measurements revealed that the N-terminal peptide of B3 is involved in interaction. PRDX2 underwent a conformational change upon its binding to B3 without losing its peroxidase activity. Hemichrome formation induced by phenylhydrazine (PHZ) of RBCs prevented membrane association of PRDX2 implying over lapping binding sites. Documentation of the absence of binding of PRDX2 to B3 Neapolis red cell membranes in which the initial N-terminal 11 amino acids are deleted, enabled us to conclude that PRDX2 binds to the N-terminal cytoplasmic domain of B3 and that the first 11 amino acid of this domain are crucial for PRDX2 membrane-association in intact RBCs. These findings imply yet another important role for B3 in regulating red cell membrane function.
    Free Radical Biology and Medicine 10/2012; 55. DOI:10.1016/j.freeradbiomed.2012.10.543 · 5.71 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The terms "neuroacanthocytosis" (NA) and "neurodegeneration with brain iron accumulation" (NBIA) both refer to groups of genetically heterogeneous disorders, classified together due to similarities of their phenotypic or pathological findings. Even collectively, the disorders that comprise these sets are exceedingly rare and challenging to study. The NBIA disorders are defined by their appearance on brain magnetic resonance imaging, with iron deposition in the basal ganglia. Clinical features vary, but most include a movement disorder. New causative genes are being rapidly identified; however, the mechanisms by which mutations cause iron accumulation and neurodegeneration are not well understood. NA syndromes are also characterized by a progressive movement disorder, accompanied by cognitive and psychiatric features, resulting from mutations in a number of genes whose roles are also basically unknown. An overlapping feature of the two groups, NBIA and NA, is the occurrence of acanthocytes, spiky red cells with a poorly-understood membrane dysfunction. In this review we summarise recent developments in this field, specifically insights into cellular mechanisms and from animal models. Cell membrane research may shed light upon the significance of the erythrocyte abnormality, and upon possible connections between the two sets of disorders. Shared pathophysiologic mechanisms may lead to progress in the understanding of other types of neurodegeneration.
    Neurobiology of Disease 03/2012; 46(3):607-24. DOI:10.1016/j.nbd.2012.03.006 · 5.20 Impact Factor