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


De Franceschi, L; Tomelleri, C; Matte, A; Brunati, A M; Bovee-Geurts, P H; Bertoldi, M; Lansoder, E; Tibaldi, E; Danek, A; Walker, R H; Jung, H H; Bader, B; Siciliano, A; Ferru, E; Mohandas, N; Bosman, G J (2011). Erythrocyte membrane changes of chorea-acanthocytosis are the result of altered Lyn kinase activity. Blood, 118(20):5652-5663.

Abstract

Acanthocytic red blood cells (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, beta-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 co-immunoprecipitation 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.

Acanthocytic red blood cells (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, beta-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 co-immunoprecipitation 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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Neurology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2011
Deposited On:07 Nov 2011 10:07
Last Modified:05 Apr 2016 15:04
Publisher:American Society of Hematology
ISSN:0006-4971
Additional Information:This research was originally published in Blood. 2011 Nov 17;118(20):5652-5663. Copyright by the American Society of Hematology.
Publisher DOI:https://doi.org/10.1182/blood-2011-05-355339
PubMed ID:21951684
Permanent URL: https://doi.org/10.5167/uzh-50706

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