Please use this identifier to cite or link to this item:
|Title:||A new molecular link between defective autophagy and erythroid abnormalities in chorea-acanthocytosis||Authors:||Lupo, Francesca
Sharma, Alok K
Brunati, Anna Maria
Alper, Seth L
Walker, Ruth H
De Franceschi, Lucia
|Keywords Plus:||ANION TRANSPORT ACTIVITY;RED-CELLS;MITOCHONDRIAL CLEARANCE;PROTEIN-PHOSPHORYLATION;MEMBRANE ASSOCIATION;MOUSE MODEL;COMPLEX;HSP90;PEROXIREDOXIN-2;DOCKING||Mesh headings:||Autophagy;Erythroid Cells;Neuroacanthocytosis||Secondary Mesh headings:||Adult;Anion Exchange Protein 1, Erythrocyte;Autophagy-Related Protein 7;Autophagy-Related Protein-1 Homolog;Benzoquinones;Bortezomib;Cell Differentiation;Cytosol;Demography;Erythrocytes;Erythropoiesis;Female;Heat-Shock Proteins;Humans;Intracellular Signaling Peptides and Proteins;Lactams, Macrocyclic;Lysosomes;Male;Middle Aged;Mitochondria;Molecular Weight;Multivesicular Bodies;Phosphorylation;Proteasome Endopeptidase Complex;Proteolysis;src-Family Kinases||Issue Date:||2016||Publisher:||AMER SOC HEMATOLOGY||Journal:||Blood||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.
|Appears in Collections:||Articles|
Show full item record
checked on May 3, 2021
checked on Aug 31, 2020
WEB OF SCIENCETM
checked on Dec 5, 2021
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.