Please use this identifier to cite or link to this item: http://hdl.handle.net/20.500.12857/116046
Title: A new molecular link between defective autophagy and erythroid abnormalities in chorea-acanthocytosis
Authors: Lupo, Francesca 
Tibaldi, Elena 
Matte, Alessandro 
Sharma, Alok K
Brunati, Anna Maria 
Alper, Seth L
Zancanaro, Carlo 
Benati, Donatella 
Siciliano, Angela 
Bertoldi, Mariarita 
Zonta, Francesca 
Storch, Alexander
Walker, Ruth H
Danek, Adrian
Bader, Benedikt
Hermann, Andreas
De Franceschi, Lucia
Keywords Plus: ANION TRANSPORT ACTIVITY;RED-CELLS;MITOCHONDRIAL CLEARANCE;PROTEIN-PHOSPHORYLATION;MEMBRANE ASSOCIATION;MOUSE MODEL;COMPLEX;HSP90;PEROXIREDOXIN-2;DOCKING
Mesh headings: Autophagy;Erythroid Cells;Neuroacanthocytosis
Secondary Mesh headings: Adult;Anion Exchange Protein 1, Erythrocyte;Autophagy-Related Protein 7;Autophagy-Related Protein-1 Homolog;Benzoquinones;Bortezomib;Cell Differentiation;Cytosol;Demography;Erythrocytes;Erythropoiesis;Female;Heat-Shock Proteins;Humans;Intracellular Signaling Peptides and Proteins;Lactams, Macrocyclic;Lysosomes;Male;Middle Aged;Mitochondria;Molecular Weight;Multivesicular Bodies;Phosphorylation;Proteasome Endopeptidase Complex;Proteolysis;src-Family Kinases
Issue Date: 2016
Publisher: AMER SOC HEMATOLOGY
Journal: Blood 
Abstract: 
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 Lyn-containing 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 CD34+-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 chorea-acanthocytosis erythroid cells an association between accumulation of active Lyn and impaired autophagy, suggesting a link between chorein and autophagic vesicle trafficking in erythroid maturation.
URI: http://hdl.handle.net/20.500.12857/116046
ISSN: 00064971
DOI: 10.1182/blood-2016-07-727321
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