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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 (2016): A new molecular link between defective autophagy and erythroid abnormalities in chorea-acanthocytosis. In: Blood, Vol. 128, No. 25: pp. 2976-2987
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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 (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;(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.