title: A new molecular link between defective autophagy and erythroid abnormalities in chorea-acanthocytosis.
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.
authors.affiliation: Department of Medicine, University of Verona and Azienda ospedaliera Universitaria Integrata di Verona, Verona, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Lupo
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Tibaldi
authors.affiliation: Department of Medicine, University of Verona and Azienda ospedaliera Universitaria Integrata di Verona, Verona, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Matte
authors.affiliation: Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
authors.forename: Alok K
authors.initials: AK
authors.lastname: Sharma
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Brunati
authors.affiliation: Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
authors.forename: Seth L
authors.initials: SL
authors.lastname: Alper
authors.affiliation: Department of Neuroscience, Biomedicine and Movement, University of Verona, Verona, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Zancanaro
authors.affiliation: Department of Neuroscience, Biomedicine and Movement, University of Verona, Verona, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Benati
authors.affiliation: Department of Medicine, University of Verona and Azienda ospedaliera Universitaria Integrata di Verona, Verona, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Siciliano
authors.affiliation: Department of Neuroscience, Biomedicine and Movement, University of Verona, Verona, Italy.
authors.forename: Mariarita
authors.initials: M
authors.lastname: Bertoldi
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Zonta
authors.affiliation: Center for Regenerative Therapies, and.|Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, Dresden, Germany.|Center for Neurodegenerative Diseases, Dresden, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Storch
authors.affiliation: Department of Neurology, James J. Peters VA Medical Center, Bronx, NY.|Mount Sinai School of Medicine, New York, NY; and.
authors.forename: Ruth H
authors.initials: RH
authors.lastname: Walker
authors.affiliation: Department of Neurology, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Adrian
authors.initials: A
authors.lastname: Danek
authors.affiliation: Department of Neurology, Ludwig-Maximilians-Universität, Munich, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Bader
authors.affiliation: Division of Neurodegenerative Diseases, Department of Neurology, Technische Universität Dresden, Dresden, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hermann
authors.affiliation: Department of Medicine, University of Verona and Azienda ospedaliera Universitaria Integrata di Verona, Verona, Italy.
authors.forename: Lucia
authors.identifier: 0000-0001-7093-777X
authors.initials: L
authors.lastname: De Franceschi
mesh_terms: D000328:Adult; D001457:Anion Exchange Protein 1, Erythrocyte / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D000071193:Autophagy-Related Protein 7 / Q000378:metabolism; D000071189:Autophagy-Related Protein-1 Homolog / Q000378:metabolism; D016227:Benzoquinones / Q000494:pharmacology; D000069286:Bortezomib / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D003710:Demography; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D041905:Erythroid Cells / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D004920:Erythropoiesis / Q000187:drug effects; D005260:Female; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008970:Molecular Weight; D057146:Multivesicular Bodies / Q000187:drug effects / Q000378:metabolism; D054546:Neuroacanthocytosis / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D001457:Anion Exchange Protein 1, Erythrocyte; D016227:Benzoquinones; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D047029:Lactams, Macrocyclic; D000069286:Bortezomib; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D000071189:Autophagy-Related Protein-1 Homolog; C484754:ULK1 protein, human; D046988:Proteasome Endopeptidase Complex; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; C001277:geldanamycin