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Blood. 2016 Dec 22;128(25):2976-2987. doi: 10.1182/blood-2016-07-727321. Epub 2016 Oct 14.

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

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Department of Medicine, University of Verona and Azienda ospedaliera Universitaria Integrata di Verona, Verona, Italy.
Department of Molecular Medicine, University of Padova, Padova, Italy.
Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
Department of Neuroscience, Biomedicine and Movement, University of Verona, Verona, Italy.
Center for Regenerative Therapies, and.
Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, Dresden, Germany.
Center for Neurodegenerative Diseases, Dresden, Germany.
Department of Neurology, James J. Peters VA Medical Center, Bronx, NY.
Mount Sinai School of Medicine, New York, NY; and.
Department of Neurology, Ludwig-Maximilians-Universität, Munich, Germany.


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.

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