title: Oxidative stress contributes to outcome severity in a Drosophila melanogaster model of classic galactosemia.
abstract: Classic galactosemia is a genetic disorder that results from profound loss of galactose-1P-uridylyltransferase (GALT). Affected infants experience a rapid escalation of potentially lethal acute symptoms following exposure to milk. Dietary restriction of galactose prevents or resolves the acute sequelae; however, many patients experience profound long-term complications. Despite decades of research, the mechanisms that underlie pathophysiology in classic galactosemia remain unclear. Recently, we developed a Drosophila melanogaster model of classic galactosemia and demonstrated that, like patients, GALT-null Drosophila succumb in development if exposed to galactose but live if maintained on a galactose-restricted diet. Prior models of experimental galactosemia have implicated a possible association between galactose exposure and oxidative stress. Here we describe application of our fly genetic model of galactosemia to the question of whether oxidative stress contributes to the acute galactose sensitivity of GALT-null animals. Our first approach tested the impact of pro- and antioxidant food supplements on the survival of GALT-null and control larvae. We observed a clear pattern: the oxidants paraquat and DMSO each had a negative impact on the survival of mutant but not control animals exposed to galactose, and the antioxidants vitamin C and α-mangostin each had the opposite effect. Biochemical markers also confirmed that galactose and paraquat synergistically increased oxidative stress on all cohorts tested but, interestingly, the mutant animals showed a decreased response relative to controls. Finally, we tested the expression levels of two transcripts responsive to oxidative stress, GSTD6 and GSTE7, in mutant and control larvae exposed to galactose and found that both genes were induced, one by more than 40-fold. Combined, these results implicate oxidative stress and response as contributing factors in the acute galactose sensitivity of GALT-null Drosophila and, by extension, suggest that reactive oxygen species might also contribute to the acute pathophysiology in classic galactosemia.
authors: Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Patricia P
authors: PP
authors: Jumbo-Lucioni
authors: Marquise L
authors: ML
authors: Hopson
authors: Darwin
authors: D
authors: Hang
authors: Yongliang
authors: Y
authors: Liang
authors: Dean P
authors: DP
authors: Jones
authors: Judith L
authors: JL
authors: Fridovich-Keil
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D003545:Cysteine / Q000378:metabolism; D004121:Dimethyl Sulfoxide / Q000633:toxicity; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D005690:Galactose / Q000378:metabolism / Q000633:toxicity; D005693:Galactosemias / Q000188:drug therapy / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D005695:Galactosephosphates / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D055786:Gene Knockout Techniques; D017344:Genes, Insect; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009154:Mutation; D018384:Oxidative Stress / Q000187:drug effects; D010269:Paraquat / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000378:metabolism; D006599:UDPglucose-Hexose-1-Phosphate Uridylyltransferase / Q000172:deficiency / Q000235:genetics; D044004:Xanthones / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D029721:Drosophila Proteins; D005695:Galactosephosphates; D017382:Reactive Oxygen Species; D044004:Xanthones; C029973:galactose-1-phosphate; D005982:Glutathione Transferase; D006599:UDPglucose-Hexose-1-Phosphate Uridylyltransferase; D005978:Glutathione; D003545:Cysteine; D010269:Paraquat; D001205:Ascorbic Acid; C021053:mangostin; D005690:Galactose; D004121:Dimethyl Sulfoxide