title: The role of peroxisomal ABC transporters in the mouse adrenal gland: the loss of Abcd2 (ALDR), Not Abcd1 (ALD), causes oxidative damage.
abstract: X-linked adreno-leukodystrophy is a progressive, systemic peroxisomal disorder that primarily affects the adrenal cortex, as well as myelin and axons of the central nervous system. Marked phenotypic heterogeneity does not correlate with disease-causing mutations in ABCD1, which encodes a peroxisomal membrane protein that is a member of the ABC transmembrane transporter proteins. The precise physiological functions of ABCD1 and ABCD2, a closely related peroxisomal membrane half-transporter, are unknown. The abcd1 knockout mouse does not develop the inflammatory demyelination so typical and devastating in adreno-leukodystrophy, but it does display the same lamellae and lipid profiles in adrenocortical cells under the electron microscope as the human patients. The adrenocortical cells in the mouse also exhibit immunohistochemical evidence of oxidative stress at 12 weeks but no evidence of oxidative damage. To better understand the pathogenesis of this complex disease, we evaluate the adrenal lesion of the abcd1 knockout mouse as a function of normal aging, dietary or therapeutic manipulations, and abcd genotype. The loss of abcd2 causes oxidative stress in the adrenal at 12 weeks, as judged by increased immunoreactivity for the mitochondrial manganese superoxide dismutase, in both the inner cortex and medulla. The loss of abcd2 (n=20), but not abcd1 (n=27), results in the spontaneous and premature deposition of ceroid, a known end-product of oxidative damage, predominantly in adrenal medullary cells. These data indicate that the loss of abcd2 results in greater oxidative stress in murine adrenal cells than the loss of abcd1, providing a clue to its cellular function. We also find that the adrenocortical lesion of the abcd1 knockout mouse does not produce functional impairment at ten to nineteen months or overt hypocortisolism at any age, nor does it progress histologically; these and other data align this mouse model closer to human female heterozygotes than to male ALD or AMN hemizygotes.
authors.affiliation: Johns Hopkins School of Medicine, Kennedy Krieger Institute, Baltimore, MD, USA.
authors.forename: Jyh-Feng
authors.initials: JF
authors.lastname: Lu
authors.forename: Emily
authors.initials: E
authors.lastname: Barron-Casella
authors.forename: Rebecca
authors.initials: R
authors.lastname: Deering
authors.forename: Ann K
authors.initials: AK
authors.lastname: Heinzer
authors.forename: Ann B
authors.initials: AB
authors.lastname: Moser
authors.forename: Karen L
authors.initials: KL
authors.lastname: deMesy Bentley
authors.forename: Gary S
authors.initials: GS
authors.lastname: Wand
authors.forename: Martina
authors.initials: M
authors.lastname: C McGuinness
authors.forename: Zhengtong
authors.initials: Z
authors.lastname: Pei
authors.forename: Paul A
authors.initials: PA
authors.lastname: Watkins
authors.forename: Aurora
authors.initials: A
authors.lastname: Pujol
authors.forename: Kirby D
authors.initials: KD
authors.lastname: Smith
authors.forename: James M
authors.initials: JM
authors.lastname: Powers
mesh_terms: D000074061:ATP Binding Cassette Transporter, Subfamily D; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000311:Adrenal Glands / Q000378:metabolism*; D000818:Animals; D054422:Chemokine CCL22; D019742:Chemokines, CC / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019314:Dehydroepiandrosterone Sulfate / Q000008:administration & dosage; D004338:Drug Combinations; D004883:Erucic Acids / Q000008:administration & dosage; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D020675:Peroxisomes / Q000378:metabolism*; D014304:Triolein / Q000008:administration & dosage
chemical_list: C508354:ABCD2 protein, mouse; D000074061:ATP Binding Cassette Transporter, Subfamily D; D018528:ATP-Binding Cassette Transporters; C515482:CCL22 protein, human; C515483:Ccl22 protein, mouse; D054422:Chemokine CCL22; D019742:Chemokines, CC; D004338:Drug Combinations; D004883:Erucic Acids; C079420:Lorenzo's oil; D014304:Triolein; D019314:Dehydroepiandrosterone Sulfate