A new molecular link between defective autophagy and erythroid abnormalities in chorea-acanthocytosis
Francesca Lupo1, Elena Tibaldi2, Alessandro Matte1
1Department of Medicine, University of Verona and Azienda ospedaliera Universitaria Integrata di Verona, Verona, Italy.
Insights
Chorea-acanthocytosis red cells show impaired autophagy and toxic Lyn accumulation. This suggests a link between chorein, Lyn, and autophagic vesicle trafficking in red blood cell maturation.
Area of Science:
- Neurobiology
- Cell Biology
- Hematology
Background:
- Chorea-acanthocytosis is a rare hereditary neurodegenerative disorder.
- It is characterized by acanthocytes (spiky red blood cells) deficient in the protein chorein.
- The function of chorein and its role in the disease are not well understood.
Purpose of the Study:
- To investigate the cellular mechanisms underlying chorea-acanthocytosis, focusing on red blood cells.
- To explore the potential role of autophagy and protein accumulation in the disease pathology.
- To determine the relationship between chorein, Lyn, and autophagic processes.
Main Methods:
- Analysis of red blood cells from chorea-acanthocytosis patients and healthy controls.
- Co-immunoprecipitation assays to study protein interactions (Lyn, Ulk1, Atg7, chorein).
- High-molecular-weight complex analysis using HSP90-70.
- Electron microscopy to visualize cellular structures.
- In vitro studies using CD34+-derived erythroid precursors.
Main Results:
- Chorea-acanthocytosis red cells exhibit impaired autophagy with cytoplasmic accumulation of active Lyn, Ulk1, and Atg7.
- Active Lyn forms stable complexes with HSP90-70, preventing its degradation and leading to toxic accumulation.
- Chorein interacts with Atg7 in healthy cells but not in chorea-acanthocytosis cells.
- Impaired autophagic flux, delayed clearance of mitochondria and lysosomes, and dyserythropoiesis were observed in patient-derived erythroid precursors.
Conclusions:
- Chorea-acanthocytosis red blood cells display a novel association between active Lyn accumulation and impaired autophagy.
- These findings suggest a critical role for chorein in autophagic vesicle trafficking during erythroid maturation.
- The study provides new insights into the molecular pathogenesis of 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.
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