Induction of HO-1 and NOS in doppel-expressing mice devoid of PrP: implications for doppel function.
Ectopic expression of the doppel (Dpl) protein, a homologue of the prion protein (PrP), was recently associated with cerebellar Purkinje cell degeneration observed in two aging prion protein knock-out (Prnp(0/0)) mouse lines. We investigated the possible role of Dpl in oxidative metabolism. Two Prnp(0/0) mouse lines of similar genetic background were studied. One line expresses Dpl in the brain and displays Dpl-associated cerebellar abnormalities. The other has no elevated expression of Dpl and no cerebellar abnormalities. We observed a correlation between Dpl expression and the induction of both heme oxygenase 1 (HO-1) and nitric oxide synthase systems (nNOS and iNOS). These responses are suggestive of increased oxidative stress in the brains of the Dpl-expressing Prnp(0/0) mice. No induction was observed with Hsp-60, indicating a specific response by the HO/NOS system. We proposed that Dpl expression exacerbates oxidative damage that is antagonistic to the protective function of wild-type PrP.
Wong
B S
BS
Institute of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio
Liu
T
T
Paisley
D
D
Li
R
R
Pan
T
T
Chen
S G
SG
Perry
G
G
Petersen
R B
RB
Smith
M A
MA
Melton
D W
DW
Gambetti
P
P
Brown
D R
DR
Sy
M S
MS
D000818:Animals; D018834:Chaperonin 60 / Q000235:genetics; D058851:GPI-Linked Proteins; D015971:Gene Expression Regulation, Enzymologic; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics*; D051547:Heme Oxygenase-1; D015227:Lipid Peroxidation / Q000502:physiology; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D011328:Prions / Q000235:genetics* / Q000378:metabolism*; D011689:Purkinje Cells / Q000201:enzymology*
D018834:Chaperonin 60; D058851:GPI-Linked Proteins; D008565:Membrane Proteins; D009573:Nitrites; D011328:Prions; C122036:Prnd protein, mouse; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; C496321:Nos1 protein, mouse; C496317:Nos2 protein, mouse; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse