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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.

Author information

1
Department of Medicine, University of Verona and Azienda ospedaliera Universitaria Integrata di Verona, Verona, Italy.
2
Department of Molecular Medicine, University of Padova, Padova, Italy.
3
Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
4
Department of Neuroscience, Biomedicine and Movement, University of Verona, Verona, Italy.
5
Center for Regenerative Therapies, and.
6
Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, Dresden, Germany.
7
Center for Neurodegenerative Diseases, Dresden, Germany.
8
Department of Neurology, James J. Peters VA Medical Center, Bronx, NY.
9
Mount Sinai School of Medicine, New York, NY; and.
10
Department of Neurology, Ludwig-Maximilians-Universität, Munich, Germany.

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.

PMID:
27742708
PMCID:
PMC5179337
DOI:
10.1182/blood-2016-07-727321
[Indexed for MEDLINE]
Free PMC Article

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