Analysis of doppel protein toxicity.
The recently described doppel protein (Dpl) is a homologue of the prion protein (PrP(c)). This protein, expressed in the brains of mice that lack the expression of PrP(c), causes neuronal death as the mice age. Previous studies have suggested this neuronal damage is caused by oxidative assault and changes in the activity of NOS proteins. We investigated the toxicity of Dpl in cell culture models and showed that Dpl was toxic to neurons. This toxicity was inhibited by the expression of PrP(c) and possibly involved direct interaction between the two proteins. The mechanism of toxicity involved stimulation of nitric oxide production via activation of the nitric oxide synthases, nNOS and iNOS. This mechanism of toxicity is quite different from that of PrP(Sc) and does not require the protein to change conformation. These results provide the first evidence for the mechanism of Dpl toxicity.
Cui
Taian
T
Department of Biology and Biochemistry, Bath University, UK.
Holme
Andrea
A
Sassoon
Judyth
J
Brown
David R
DR
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D002942:Circular Dichroism; D058851:GPI-Linked Proteins; D015870:Gene Expression; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009410:Nerve Degeneration / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000166:cytology*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D018384:Oxidative Stress / Q000502:physiology; D010446:Peptide Fragments / Q000633:toxicity; D018621:PrPC Proteins / Q000235:genetics / Q000378:metabolism; D011328:Prions / Q000235:genetics* / Q000378:metabolism / Q000633:toxicity*
D058851:GPI-Linked Proteins; D010446:Peptide Fragments; D018621:PrPC Proteins; D011328:Prions; C122036:Prnd protein, mouse; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; C496321:Nos1 protein, mouse; C496317:Nos2 protein, mouse