Prion protein fragment 106-126 differentially induces heme oxygenase-1 mRNA in cultured neurons and astroglial cells.
Heme oxygenase (HO), which catalyzes the degradation of heme, has two isozymes (HO-1 and HO-2). In brain the noninducible HO-2 isoform is predominant, whereas the inducible HO-1 is a marker of oxidative stress. Because brain oxidative stress might be present in prion-related encephalopathies (PREs), as in other neurodegenerative diseases, we investigated whether HO-1 mRNA was induced in neuronal and astroglial cell cultures by a peptide corresponding to residue 106-126 of human prion protein (PrP). This peptide is amyloidogenic, and when added in vitro to cultured cells it reproduces the neuronal death and astroglial proliferation and hypertrophy occurring in PREs. HO-1 mRNA did not accumulate in rat cultured neurons from hippocampus or cortex exposed to PrP 106-126 (50 microM for 5 days). PrP 106-126 induced HO-1 mRNA accumulation in rat astroglial cultures depending on the exposure time and concentration, being maximal (33-fold) after 7 days of exposure at 50 microM. The nonamyloidogenic amidated or amidated-acetylated PrP 106-126 was ineffective, as was a scrambled peptide used as control. N-Acetylcysteine reduced (50%) the accumulation of HO-1 mRNA in astroglial cells after PrP 106-126 (25 microM) given for 5 days. Thus, oxidative stress is apparently a feature of the toxicity of PrP 106-126, and it might also occur in PREs; induction of HO-1 could contribute to the greater resistance of astrocytes compared with neurons to PrP 106-126 toxicity.
Rizzardini
M
M
Heme and Hemoprotein Unit, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Chiesa
R
R
Angeretti
N
N
Lucca
E
E
Salmona
M
M
Forloni
G
G
Cantoni
L
L
D000111:Acetylcysteine / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology*; D015152:Blotting, Northern; D002478:Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D002540:Cerebral Cortex / Q000166:cytology; D016166:Free Radical Scavengers / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics*; D006624:Hippocampus / Q000166:cytology; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology*; D011328:Prions / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats
D016166:Free Radical Scavengers; D010446:Peptide Fragments; D011328:Prions; D012333:RNA, Messenger; C082632:prion protein (106-126); D006419:Heme Oxygenase (Decyclizing); D000111:Acetylcysteine