title: Manganese-based superoxide dismutase mimics modify both acute and long-term outcome severity in a Drosophila melanogaster model of classic galactosemia.
abstract: OBJECTIVE
  The goal of this study was to use two manganese (Mn)-based superoxide dismutase (SOD) mimics to test the hypothesis that reactive oxygen species contribute to both acute and long-term outcomes in a galactose-1P uridylyltransferase (GALT)-null Drosophila melanogaster model of classic galactosemia.
  
  
  RESULTS
  We tested the impact of each of two Mn porphyrin SOD mimics, MnTnBuOE-2-PyP(5+), and MnTE-2-PyP(5+), (i) on survival of GALT-null Drosophila larvae reared in the presence versus absence of dietary galactose and (ii) on the severity of a long-term movement defect in GALT-null adult flies. Both SOD mimics conferred a significant survival benefit to GALT-null larvae exposed to galactose but not to controls or to GALT-null larvae reared in the absence of galactose. One mimic, MnTE-2-PyP(5+), also largely rescued a galactose-independent long-term movement defect otherwise seen in adult GALT-null flies. The survival benefit of both SOD mimics occurred despite continued accumulation of elevated galactose-1P in the treated animals, and studies of thiolated proteins demonstrated that in both the presence and absence of dietary galactose MnTE-2-PyP(5+) largely prevented the elevated protein oxidative damage otherwise seen in GALT-null animals relative to controls.
  
  
  CONCLUSIONS
  Our results confirm oxidative stress as a mediator of acute galactose sensitivity in GALT-null Drosophila larvae and demonstrate for the first time that oxidative stress may also contribute to galactose-independent adult outcomes in GALT deficiency. Finally, our results demonstrate for the first time that both MnTnBuOE-2-PyP(5+) and MnTE-2-PyP(5+) are bioavailable and effective when administered through an oral route in a D. melanogaster model of classic galactosemia.
authors.affiliation: 1 Department of Human Genetics, Emory University School of Medicine , Atlanta, Georgia .
authors.forename: Patricia P
authors.initials: PP
authors.lastname: Jumbo-Lucioni
authors.forename: Emily L
authors.initials: EL
authors.lastname: Ryan
authors.forename: Marquise L
authors.initials: ML
authors.lastname: Hopson
authors.forename: Heather M
authors.initials: HM
authors.lastname: Bishop
authors.forename: Tin
authors.initials: T
authors.lastname: Weitner
authors.forename: Artak
authors.initials: A
authors.lastname: Tovmasyan
authors.forename: Ivan
authors.initials: I
authors.lastname: Spasojevic
authors.forename: Ines
authors.initials: I
authors.lastname: Batinic-Haberle
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Liang
authors.forename: Dean P
authors.initials: DP
authors.lastname: Jones
authors.forename: Judith L
authors.initials: JL
authors.lastname: Fridovich-Keil
mesh_terms: D000818:Animals; D003545:Cysteine / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D004331:Drosophila melanogaster; D005690:Galactose / Q000378:metabolism; D005693:Galactosemias / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D005978:Glutathione / Q000097:blood / Q000378:metabolism; D008297:Male; D053858:Metabolic Networks and Pathways; D008665:Metalloporphyrins / Q000493:pharmacokinetics / Q000494:pharmacology; D018716:Molecular Mimicry; D010084:Oxidation-Reduction / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D008665:Metalloporphyrins; C575143:Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D005978:Glutathione; D003545:Cysteine; D005690:Galactose