title: FTY720 protects neuronal cells from damage induced by human prion protein by inactivating the JNK pathway.
abstract: Prion diseases affect the central nervous system (CNS) in humans and animals, and are associated with the conversion of the cellular prion protein (PrPC) to the misfolded isoform (PrPSc). FTY720, an immune modulator and synthetic analogue of sphingosine-1-phosphate (S1P), activates S1P receptors and has been shown to be effective in experimental models of transplantation and autoimmunity, including multiple sclerosis. Whereas the immune modulatory functions of FTY720 have been extensively investigated, the other functions of FTY720 are not yet well understood. In this study, we investigated the effects of FTY720 phosphate (FTY720-p) on prion protein-mediated neuronal cell death, as well as its effects on intracellular apoptotic pathways. Treatment with FTY720-p protected neuronal cells from synthetic human prion protein peptide [PrP (106‑126)]-mediated damage and prevented mitochondrial dysfunction by inhibiting the activation of c-jun N-terminal kinase. Moreover, FTY720-p prevented the PrP (106‑126)-induced reduction in mitochondrial potential, the translocation of Bax to the mitochondria and the release of cytochrome c. To the best of our knowledge, this study is the first to demonstrate the effects of FTY720 on prion protein-mediated neurotoxicity and to suggest that FTY720 has therapeutic potential in prion diseases.
authors.affiliation: Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Jeonju, Jeonbuk 561-756, Republic of Korea.
authors.forename: Myung-Hee
authors.initials: MH
authors.lastname: Moon
authors.forename: Jae-Kyo
authors.initials: JK
authors.lastname: Jeong
authors.forename: You-Jin
authors.initials: YJ
authors.lastname: Lee
authors.forename: Sang-Youel
authors.initials: SY
authors.lastname: Park
mesh_terms: D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D000068876:Fingolimod Hydrochloride; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity; D010446:Peptide Fragments / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D011328:Prions / Q000633:toxicity*; D011409:Propylene Glycols / Q000494:pharmacology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D018696:Neuroprotective Agents; D009498:Neurotoxins; D010446:Peptide Fragments; D011328:Prions; D011409:Propylene Glycols; C082632:prion protein (106-126); D048031:JNK Mitogen-Activated Protein Kinases; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine