Increased transcription and activity of glutathione synthase in response to deficiencies in folate, vitamin E, and apolipoprotein E.
Oxidative stress is a major contributing factor in neurodegeneration and can arise from dietary, environmental, and genetic sources. Here we examine the separate and combined impact of deprivation of folate and vitamin E, coupled with dietary iron as a prooxidant, on normal mice and transgenic mice lacking apolipoprotein E (ApoE-/- mice). Both mouse strains exhibited increased levels of glutathione when deprived of folate and vitamin E, but a substantial further increase was observed in ApoE-/- mice. To determine the mechanism(s) underlying this increase, we quantified transcription and activity of glutathione synthase (GS). Both normal and ApoE-/- mice demonstrated increased GS activity when deprived of folate and vitamin E. However, transcription was increased only in ApoE-/- mice deprived of folate and vitamin E. These findings demonstrate that deficiency in one gene can result in compensatory up-regulation in a second relevant gene and, furthermore, indicate that compensation for oxidative stress can occur in brain tissue at epigenetic and genetic levels depending on the nature and/or extent of oxidative stress.
Tchantchou
Flaubert
F
Center for Cellular Neurobiology and Neurodegeneration Research, University of Massachusetts--Lowell, Massachusetts 01854, USA.
Graves
Michael
M
Ashline
David
D
Morin
Amy
A
Pimenta
Aurea
A
Ortiz
Daniela
D
Rogers
Eugene
E
Shea
Thomas B
TB
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D004789:Enzyme Activation / Q000502:physiology; D005494:Folic Acid Deficiency / Q000235:genetics / Q000378:metabolism*; D005981:Glutathione Synthase / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D014158:Transcription, Genetic / Q000502:physiology*; D014811:Vitamin E Deficiency / Q000235:genetics / Q000378:metabolism*
D001057:Apolipoproteins E; D005981:Glutathione Synthase