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, 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 co-immunoprecipitation 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-microscopic 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. Since 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;(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.
| Item Type: | Journal article |
|---|---|
| Faculties: | Medicine |
| Subjects: | 600 Technology > 610 Medicine and health |
| ISSN: | 0006-4971 |
| Language: | English |
| Item ID: | 46010 |
| Date Deposited: | 27. Apr 2018, 08:10 |
| Last Modified: | 04. Nov 2020, 13:22 |
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