A new molecular link between defective autophagy and erythroid abnormalities in chorea-acanthocytosis.
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.
Mesh Terms:
Adult, Anion Exchange Protein 1, Erythrocyte, Autophagy, Autophagy-Related Protein 7, Autophagy-Related Protein-1 Homolog, Benzoquinones, Bortezomib, Cell Differentiation, Cytosol, Demography, Erythrocytes, Erythroid Cells, Erythropoiesis, Female, Heat-Shock Proteins, Humans, Intracellular Signaling Peptides and Proteins, Lactams, Macrocyclic, Lysosomes, Male, Middle Aged, Mitochondria, Molecular Weight, Multivesicular Bodies, Neuroacanthocytosis, Phosphorylation, Proteasome Endopeptidase Complex, Proteolysis, src-Family Kinases
Adult, Anion Exchange Protein 1, Erythrocyte, Autophagy, Autophagy-Related Protein 7, Autophagy-Related Protein-1 Homolog, Benzoquinones, Bortezomib, Cell Differentiation, Cytosol, Demography, Erythrocytes, Erythroid Cells, Erythropoiesis, Female, Heat-Shock Proteins, Humans, Intracellular Signaling Peptides and Proteins, Lactams, Macrocyclic, Lysosomes, Male, Middle Aged, Mitochondria, Molecular Weight, Multivesicular Bodies, Neuroacanthocytosis, Phosphorylation, Proteasome Endopeptidase Complex, Proteolysis, src-Family Kinases
Blood
Date: Dec. 22, 2015
PubMed ID: 27742708
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