title: The cellular prion protein (PrPC) prevents apoptotic neuronal cell death and mitochondrial dysfunction induced by serum deprivation.
abstract: Prion diseases are transmissible neurodegenerative disorders that are invariably fatal in humans and animals. Although the nature of the infectious agent and pathogenic mechanisms of prion diseases are not clear, it has been reported that prion diseases may be associated with aberrant metabolism of cellular prion protein (PrP(C)). In various reports, it has been postulated that PrP(C) may be involved in one or more of the following: neurotransmitter metabolism, cell adhesion, signal transduction, copper metabolism, antioxidant activity or programmed cell death. Despite suggestive results supporting each of these mechanisms, the physiological function(s) of PrP(C) is not known. To investigate whether PrP(C) can prevent apoptotic cell death in prion diseases, we established the cell lines stably expressing PrP(C) from PrP knockout (PrP(-/-)) neuronal cells and examined the role of PrP(C) under apoptosis and/or serum-deprived condition. We found that PrP(-/-) cells were vulnerable to apoptotic cell death and that this vulnerability was rescued by the expression of PrP(C). The expression levels of apoptosis-related proteins including p53, Bax, caspase-3, poly(ADP-ribose) polymerase (PARP) and cytochrome c were significantly increased in PrP(-/-) cells. In addition, Ca(2+) levels of mitochondria were increased, whereas mitochondrial membrane potentials were decreased in PrP(-/-) cells. These results strongly suggest that PrP(C) may play a central role as an effective anti-apoptotic protein through caspase-dependent apoptotic pathways in mitochondria, supporting the concept that disruption of PrP(C) and consequent reduction of anti-apoptotic capacity of PrP(C) may be one of the pathogenic mechanisms of prion diseases.
authors.affiliation: Ilsong Institute of Life Science, Hallym Academy of Sciences, Hallym University, Ilsong Building, Kwanyang-dong 1605-4, Dongan-gu, Anyang 431-060, South Korea.
authors.forename: Boe-Hyun
authors.initials: BH
authors.lastname: Kim
authors.forename: Hyoung-Gon
authors.initials: HG
authors.lastname: Lee
authors.forename: Jin-Kyu
authors.initials: JK
authors.lastname: Choi
authors.forename: Jae-Il
authors.initials: JI
authors.lastname: Kim
authors.forename: Eun-Kyoung
authors.initials: EK
authors.lastname: Choi
authors.forename: Richard I
authors.initials: RI
authors.lastname: Carp
authors.forename: Yong-Sun
authors.initials: YS
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western / Q000379:methods; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005452:Fluoresceins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence / Q000379:methods; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D016133:Polymerase Chain Reaction / Q000379:methods; D018621:PrPC Proteins / Q000235:genetics / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D044967:Serum / Q000378:metabolism*; D013217:Starvation; D013997:Time Factors; D014162:Transfection / Q000379:methods; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein
chemical_list: C494827:Bax protein, mouse; D005452:Fluoresceins; D008562:Membrane Glycoproteins; D018621:PrPC Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D002118:Calcium