title: Analysis of alpha hemoglobin stabilizing protein overexpression in murine β-thalassemia.
abstract: Excess free alpha-globin is cytotoxic and contributes to the pathophysiology of b-thalassemia. Alpha hemoglobin stabilizing protein (AHSP) is a molecular chaperone that binds free alpha-globin to promote its folding and inhibit its ability to produce damaging reactive oxygen species. Reduced AHSP levels correlate with increased severity of b-thalassemia in some human cohorts, but causal mechanistic relationships are not established for these associations. We used transgenic and lentiviral gene transfer methods to investigate whether supraphysiologic AHSP levels could mitigate the severity of b-thalassemia intermedia by providing an increased sink for the excess pool of alpha-globin chains. We tested wild-type AHSP and two mutant versions with amino acid substitutions that confer 3- or 13-fold higher affinity for alpha-globin. Erythroid overexpression of these AHSP proteins up to 11-fold beyond endogenous levels had no major effects on hematologic parameters in b-thalassemic animals. Our results demonstrate that endogenous AHSP is not limiting for a-globin detoxification in a murine model of b-thalassemia.
authors.forename: Md
authors.initials: M
authors.lastname: Nasimuzzaman
authors.forename: Eugene
authors.initials: E
authors.lastname: Khandros
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Wang
authors.forename: Yi
authors.initials: Y
authors.lastname: Kong
authors.forename: Huifen
authors.initials: H
authors.lastname: Zhao
authors.forename: David
authors.initials: D
authors.lastname: Weiss
authors.forename: Stefano
authors.initials: S
authors.lastname: Rivella
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Weiss
authors.forename: Derek A
authors.initials: DA
authors.lastname: Persons
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001798:Blood Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D004909:Erythrocyte Indices; D041905:Erythroid Cells / Q000378:metabolism; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics / Q000502:physiology*; D011828:Radiation Chimera; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013045:Species Specificity; D055542:alpha-Globins / Q000378:metabolism*; D017086:beta-Thalassemia / Q000097:blood* / Q000235:genetics / Q000503:physiopathology
chemical_list: C468768:AHSP protein, human; C511177:Ahsp protein, mouse; D001798:Blood Proteins; D006454:Hemoglobins; D018832:Molecular Chaperones; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D055542:alpha-Globins
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