Oligodendrocytes are susceptible to apoptotic cell death induced by prion protein-derived peptides.
Neurodegenerative prion diseases, characterized by a progressive dementia, are associated with the accumulation of abnormal forms of the prion (PrPc) protein, potentially due to an aberrant regulation of PrPc biogenesis and/or topology. One of these forms, termed ctmPrP, displays a transmembrane conformation and might trigger neuronal cell death in Gerstmann-Straüssler-Scheinker (GSS) syndrome and other prion-associated diseases in humans. Although the primary target cells involved in the progression of prion diseases remain unidentified, it was recently suggested that modifications of the oligodendroglial cells occur early in prion diseases. In the present study, we demonstrate that a putative transmembrane domain of the human PrPc, i.e., amino acids 118-135, induces oligodendrocyte (OLG) death in vitro in a time- and dose-dependent manner. The process leading to OLG death and induced by the PrP[118-135] peptide was characterized by DNA fragmentation, cytoskeletal disruption, and caspase activation. Protection against the PrP[118-135] peptide-induced OLG apoptosis by several antioxidant molecules, such as probucol, propylgallate, and promethazine, suggests that oxidative injuries contribute to the PrP[118-135] cytotoxicity to OLGs. These results suggest a potential pathophysiological role of the ctmPrP- and/or PrP fragment-mediated OLG cytotoxicity in spongiform encephalopathies.
Sponne
Isabelle
I
INSERM EMI 0014, Université de Nancy I, Vandoeuvre, France.
Fifre
Alexandre
A
Koziel
Violette
V
Kriem
Badreddine
B
Oster
Thierry
T
Olivier
Jean-Luc
JL
Pillot
Thierry
T
D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D053938:DNA Fragmentation / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000378:metabolism* / Q000633:toxicity; D018621:PrPC Proteins / Q000378:metabolism; D017096:Prion Diseases / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D011328:Prions / Q000378:metabolism* / Q000633:toxicity; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
D000975:Antioxidants; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D018621:PrPC Proteins; D011328:Prions; C417023:prion protein (118-135); D020169:Caspases