title: Prion peptide-mediated cellular prion protein overexpression and neuronal cell death can be blocked by aspirin treatment.
abstract: Prion diseases are infectious neurodegenerative disorders characterized by the conversion of the cellular prion protein (PrPc) to the misfolded isoform (PrPsc). Prion peptide PrP 106-126 [PrP (106-126)] shares many physiological properties with PrPsc; it is neurotoxic in vitro and in vivo. PrP (106-126) induces neurotoxicity by the overexpression of PrPc and activation of the mitogen-activated protein (ERK1/2). Aspirin, an anti-inflammatory drug, is a known ERK inhibitor and prevents neurodegenerative disorders including prion diseases. The influence of aspirin treatment on prion protein-mediated neurotoxicity and expression of PrPc were the focus of this study. Cell viability and apoptosis were assessed by crystal violet staining and the TUNEL and DNA fragmentation assays. Apoptosis-associated protein expression of PrPc, p-53, p-ERK1/2, p-p38, Bcl-2 and cleaved-caspase-3 was examined by Western blotting and immunocytochemistry. Aspirin treatment inhibited PrP (106-126)-induced neuronal cell death in SH-SY5Y neuroblastoma cells. In addition, the PrP (106-126)-mediated increase of p-p38, p53, cleaved-caspase-3 and decrease of Bcl-2 expressions were blocked by aspirin and the ERK inhibitor, PR98059. Furthermore, we showed that the PrP (106-126)-mediated increase of PrPc and p-ERK1/2 were inhibited by PD98059 and aspirin. Taken together, these results demonstrate that ERK1/2 is a key modulator of the protective effect of aspirin on PrP-106-126-mediated cellular prion protein overexpression and neurotoxicity and also suggest that aspirin may prevent neuron cell damages caused by the prion peptide.
authors.affiliation: College of Veterinary Medicine, Bio-Safety Research Institute, Center for Healthcare Technology Development, Chonbuk National University, Jeonju, Jeonbuk 561-756, Republic of Korea.
authors.forename: Jae-Kyo
authors.initials: JK
authors.lastname: Jeong
authors.forename: Myung-Hee
authors.initials: MH
authors.lastname: Moon
authors.forename: Jae-Won
authors.initials: JW
authors.lastname: Seol
authors.forename: Jae-Suk
authors.initials: JS
authors.lastname: Seo
authors.forename: You-Jin
authors.initials: YJ
authors.lastname: Lee
authors.forename: Sang-Youel
authors.initials: SY
authors.lastname: Park
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001241:Aspirin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation; D018621:PrPC Proteins / Q000378:metabolism*; D011328:Prions / Q000494:pharmacology*; D015398:Signal Transduction
chemical_list: D051017:Apoptosis Regulatory Proteins; D010446:Peptide Fragments; D018621:PrPC Proteins; D011328:Prions; C082632:prion protein (106-126); D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D001241:Aspirin