The neurotoxicity of prion protein (PrP) peptide 106-126 is independent of the expression level of PrP and is not mediated by abnormal PrP species.
A synthetic peptide homologous to region 106-126 of the prion protein (PrP) is toxic to cells expressing PrP, but not to PrP knockout neurons, arguing for a specific role of PrP in mediating the peptide's activity. Whether this is related to a gain of toxicity or a loss of function of PrP is not clear. We explored the possibility that PrP106-126 triggered formation of PrP(Sc) or other neurotoxic PrP species. We found that PrP106-126 did not induce detergent-insoluble and protease-resistant PrP, nor did it alter its membrane topology or cellular distribution. We also found that neurons expressing endogenous or higher level of either wild-type PrP or a nine-octapeptide insertional mutant were equally susceptible to PrP106-126, and that sub-physiological PrP expression was sufficient to restore vulnerability to the peptide. These results indicate that PrP106-126 interferes with a PrP function that requires only low protein levels, and is not impaired by a pathogenic insertion in the octapeptide region.
Fioriti
Luana
L
Dulbecco Telethon Institute, Istituto di Ricerche Farmacologiche Mario Negri, Milan 20157, Italy.
Quaglio
Elena
E
Massignan
Tania
T
Colombo
Laura
L
Stewart
Richard S
RS
Salmona
Mario
M
Harris
David A
DA
Forloni
Gianluigi
G
Chiesa
Roberto
R
D000818:Animals; D000831:Animals, Newborn; D002451:Cell Compartmentation / Q000235:genetics; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D006224:Cricetinae; D003600:Cytosol / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D020932:Nerve Growth Factor / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009498:Neurotoxins / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D017096:Prion Diseases / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D011328:Prions / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D051381:Rats
D009498:Neurotoxins; D010446:Peptide Fragments; D011328:Prions; C082632:prion protein (106-126); D020932:Nerve Growth Factor