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

Franceschi, Lucia De; Tomelleri, Carlo; Mattè, Alessandro; Brunati, Anna Maria; Bovée-Geurts, Petra H. M.; Bertoldi, Mariarita; Lasonder, Edwin; Tibaldi, Elena; Danek, Adrian; Walker, Ruth H.; Jung, Hans H.; Bader, Benedikt; Siciliano, Angela; Ferru, Emanuela; Mohandas, Narla; Bosman, G.J.C.G.M.

doi:10.1182/blood-2011-05-355339

Cited by 75 publications

(101 citation statements)

References 46 publications

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“…1SA, 1SB). The combined treatment with Na-vanadate and diamide produced highest levels of phosphorylation of Tyr-8 on band 3 in agreement with previous reports [29,30].…”

Section: Prdx2supporting

confidence: 81%

“…Whenever indicated Na 3 VO 4 (0.1 mM) was present in the incubation media [21]. Details are reported in Supplementary Materials and Methods.…”

Section: Treatment Of Red Cells With Different Oxidative Agents and Cmentioning

confidence: 99%

“…We therefore evaluated whether membrane association of PRDX2 in red cell is affected following treatment with Na-vanadate, a phosphatase(s) inhibitor [29,30] or by binding of deoxyhemoglobin to bind to band 3 following deoxygenation [31]. Two Tyr-residues (Tyr 8 and 21) present in N-terminal domain of band 3 are targets of Syk-Lyn tyrosine kinase pathway [30].…”

Section: Prdx2mentioning

confidence: 99%

“…Red cells underwent to treatment with two different oxidative agents diamide (2 mM) and phenylhydrazine (PHZ 100 PM) based on preliminary dose response studies and previously reported data in both human and mouse erythrocytes [18,21,22]. Whenever indicated Na 3 VO 4 (0.1 mM) was present in the incubation media [21].…”

Section: Treatment Of Red Cells With Different Oxidative Agents and Cmentioning

confidence: 99%

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Membrane association of peroxiredoxin-2 in red cells is mediated by the N-terminal cytoplasmic domain of band 3

Mattè

Bertoldi

Mohandas

et al. 2013

Free Radical Biology and Medicine

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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-plasmonresonance analysis, and proteolytic digestion assays, we document that the anti-oxidant protein,

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“…1SA, 1SB). The combined treatment with Na-vanadate and diamide produced highest levels of phosphorylation of Tyr-8 on band 3 in agreement with previous reports [29,30].…”

Section: Prdx2supporting

confidence: 81%

“…Whenever indicated Na 3 VO 4 (0.1 mM) was present in the incubation media [21]. Details are reported in Supplementary Materials and Methods.…”

Section: Treatment Of Red Cells With Different Oxidative Agents and Cmentioning

confidence: 99%

Section: Prdx2mentioning

confidence: 99%

Section: Treatment Of Red Cells With Different Oxidative Agents and Cmentioning

confidence: 99%

See 2 more Smart Citations

Membrane association of peroxiredoxin-2 in red cells is mediated by the N-terminal cytoplasmic domain of band 3

Mattè

Bertoldi

Mohandas

et al. 2013

Free Radical Biology and Medicine

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“…We recently reported that chorea-acanthocytosis erythrocytes exhibit abnormal phosphorylation of the integral membrane protein and spectrin-based cytoskeletal anchor, band 3, by the Src family tyrosine kinase (SFK) Lyn. 13,14 In addition, the observation of acanthocytes in genetically engineered mice expressing constitutively active Lyn 15 supports the importance of Lyn signaling in the dysregulation of protein-protein interactions underlying the membrane-cytoskeletal network that generates abnormally shaped erythrocytes.…”

Section: Introductionmentioning

confidence: 88%

A new molecular link between defective autophagy and erythroid abnormalities in chorea-acanthocytosis

Lupo

Tibaldi

Mattè

et al. 2016

Blood

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Key Points• In chorea-acanthocytosis, spiculated red cells are characterized by heightened Lyn kinase activity and dysregulated autophagy.• Regulation of protein turnover by autophagy plays a key role in erythropoiesis and red cell integrity.Chorea-acanthocytosis is one of the hereditary neurodegenerative disorders known as the neuroacanthocytoses. Chorea-acanthocytosis is characterized by circulating acanthocytes deficient in chorein, a protein of unknown function. We report here for the first time that chorea-acanthocytosis red cells are characterized by impaired autophagy, with cytoplasmic accumulation of active Lyn and of autophagy-related proteins Ulk1 and Atg7. In chorea-acanthocytosis erythrocytes, active Lyn is sequestered by HSP90-70 to form high-molecular-weight complexes that stabilize and protect Lyn from its proteasomal degradation, contributing to toxic Lyn accumulation. An interplay between accumulation of active Lyn and autophagy was found in chorea-acanthocytosis based on Lyn coimmunoprecipitation with Ulk1 and Atg7 and on the presence of Ulk1 in Lyncontaining high-molecular-weight complexes. In addition, chorein associated with Atg7 in healthy but not in chorea-acanthocytosis erythrocytes. Electron microscopy detected multivesicular bodies and membrane remnants only in circulating chorea-acanthocytosis red cells. In addition, reticulocyte-enriched chorea-acanthocytosis red cell fractions exhibited delayed clearance of mitochondria and lysosomes, further supporting the impairment of authophagic flux. Because autophagy is also important in erythropoiesis, we studied in vitro CD341 -derived erythroid precursors. In chorea-acanthocytosis, we found (1) dyserythropoiesis; (2) increased active Lyn; (3) accumulation of a marker of autophagic flux and autolysososme degradation; (4) accumlation of Lamp1, a lysosmal membrane protein, and LAMP1-positive aggregates; and (5) reduced clearance of lysosomes and mitochondria. Our results uncover in choreaacanthocytosis erythroid cells an association between accumulation of active Lyn and impaired autophagy, suggesting a link between chorein and autophagic vesicle trafficking in erythroid maturation. (Blood. 2016;128(25):2976-2987

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PKAN neurodegeneration and residual PANK2 activities in patient erythrocytes

Werning

Müllner

Mlynek

et al. 2020

Ann Clin Transl Neurol

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Objective Pantothenate kinase 2‐associated neurodegeneration (PKAN) is a rare neurodegenerative disease caused by mutations in the pantothenate kinase 2 (PANK2) gene. PKAN is associated with iron deposition in the basal ganglia and, occasionally, with the occurrence of misshaped erythrocytes (acanthocytes). The aim of this study was to assess residual activity of PANK2 in erythrocytes of PKAN patients and to correlate these data with the type of PANK2 mutations and the progression of neurodegeneration. Methods Residual PANK2 activities in erythrocytes of 14 PKAN patients and 14 related carriers were assessed by a radiometric assay. Clinical data on neurodegeneration included the Barry–Albright Dystonia Scale (BAD‐Scale) besides further general patient features. A molecular visualization and analysis program was used to rationalize the influence of the PKAN causing mutations on a molecular level. Results Erythrocytes of PKAN patients had markedly reduced or no PANK2 activity. However, patients with at least one allele of the c.1583C > T (T528M) or the c.833G > T (R278L) variant exhibited 12–56% of residual PANK2 activity. In line, molecular modeling indicated only minor effects on enzyme structure for these point mutations. On average, these patients with c.1583C > T or c.833G > T variant had lower BAD scores corresponding to lower symptom severity than patients with other PANK2 point mutations. Interpretation Residual erythrocyte PANK2 activity could be a predictor for the progression of neurodegeneration in PKAN patients. Erythrocytes are an interesting patient‐derived cell system with still underestimated diagnostic potential.

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

Cited by 75 publications

References 46 publications

Membrane association of peroxiredoxin-2 in red cells is mediated by the N-terminal cytoplasmic domain of band 3

Membrane association of peroxiredoxin-2 in red cells is mediated by the N-terminal cytoplasmic domain of band 3

A new molecular link between defective autophagy and erythroid abnormalities in chorea-acanthocytosis

PKAN neurodegeneration and residual PANK2 activities in patient erythrocytes

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