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, 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 co-immunoprecipitation 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-microscopic 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. Since autophagy is also important in erythropoiesis, we studied in vitro CD34+ derived erythroid precursors. In chorea-acanthocytosis, we found (i) dyserythropoiesis; (ii) increased active Lyn, (iii) accumulation of, a marker of autophagic flux and autolysososme degradation; (iv) accumlation of Lamp1, a lysosmal membrane protein, and LAMP1 positive aggregates; (iv) 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.

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

Lupo, Francesca;MATTE', Alessandro;ZANCANARO, Carlo;BENATI, Donatella;SICILIANO, Angela;BERTOLDI, Mariarita;DE FRANCESCHI, Lucia
2016-01-01

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, 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 co-immunoprecipitation 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-microscopic 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. Since autophagy is also important in erythropoiesis, we studied in vitro CD34+ derived erythroid precursors. In chorea-acanthocytosis, we found (i) dyserythropoiesis; (ii) increased active Lyn, (iii) accumulation of, a marker of autophagic flux and autolysososme degradation; (iv) accumlation of Lamp1, a lysosmal membrane protein, and LAMP1 positive aggregates; (iv) 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.
2016
Chorea-acanthocytosis; autophagy; Lyn kinase activity; erythropoiesis; red cell integrity
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11562/957314
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