| First Author | Lechauve C | Year | 2019 |
| Journal | Sci Transl Med | Volume | 11 |
| Issue | 506 | PubMed ID | 31434755 |
| Mgi Jnum | J:278703 | Mgi Id | MGI:6357805 |
| Doi | 10.1126/scitranslmed.aav4881 | Citation | Lechauve C, et al. (2019) The autophagy-activating kinase ULK1 mediates clearance of free alpha-globin in beta-thalassemia. Sci Transl Med 11(506) |
| abstractText | In beta-thalassemia, accumulated free alpha-globin forms intracellular precipitates that impair erythroid cell maturation and viability. Protein quality control systems mitigate beta-thalassemia pathophysiology by degrading toxic free alpha-globin, although the associated mechanisms are poorly understood. We show that loss of the autophagy-activating Unc-51-like kinase 1 (Ulk1) gene in beta-thalassemic mice reduces autophagic clearance of alpha-globin in red blood cell precursors and exacerbates disease phenotypes, whereas inactivation of the canonical autophagy-related 5 (Atg5) gene has relatively minor effects. Systemic treatment with the mTORC1 inhibitor rapamycin reduces alpha-globin precipitates and lessens pathologies in beta-thalassemic mice via an ULK1-dependent pathway. Similarly, rapamycin reduces free alpha-globin accumulation in erythroblasts derived from CD34(+) cells of beta-thalassemic individuals. Our findings define a drug-regulatable pathway for ameliorating beta-thalassemia. |
