title: Hinokitiol protects primary neuron cells against prion peptide-induced toxicity via autophagy flux regulated by hypoxia inducing factor-1.
abstract: Prion diseases are fatal neurodegenerative disorders that are derived from structural changes of the native PrPc. Recent studies indicated that hinokitiol induced autophagy known to major function that keeps cells alive under stressful conditions. We investigated whether hinokitiol induces autophagy and attenuates PrP (106-126)-induced neurotoxicity. We observed increase of LC3-II protein level, GFP-LC3 puncta by hinokitiol in neuronal cells. Addition to, electron microscopy showed that hinokitiol enhanced autophagic vacuoles in neuronal cells. We demonstrated that hinokitiol protects against PrP (106-126)-induced neurotoxicity via autophagy by using autophagy inhibitor, wortmannin and 3MA, and ATG5 small interfering RNA (siRNA). We checked hinokitiol activated the hypoxia-inducible factor-1α (HIF-1α) and identified that hinokitiol-induced HIF-1α regulated autophagy. Taken together, this study is the first report demonstrating that hinokitiol protected against prion protein-induced neurotoxicity via autophagy regulated by HIF-1α. We suggest that hinokitiol is a possible therapeutic strategy in neuronal disorders including prion disease.
authors.affiliation: Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk, South Korea.
authors.forename: Ji-Hong
authors.initials: JH
authors.lastname: Moon
authors.affiliation: Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk, South Korea.
authors.forename: Ju-Hee
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk, South Korea.
authors.forename: You-Jin
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk, South Korea.
authors.forename: Sang-Youel
authors.initials: SY
authors.lastname: Park
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000378:metabolism; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D000071187:Autophagy-Related Protein 5 / Q000235:genetics; D002478:Cells, Cultured; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D046529:Microscopy, Electron, Transmission; D039821:Monoterpenes / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000502:physiology*; D061251:Primary Cell Culture; D017096:Prion Diseases / Q000188:drug therapy*; D011328:Prions / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects; D014334:Tropolone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D039821:Monoterpenes; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011328:Prions; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; C082632:prion protein (106-126); C025946:3-methyladenine; D014334:Tropolone; D000225:Adenine; C009479:beta-thujaplicin; D000077191:Wortmannin
keywords: Gerotarget; HIF-1; autophagy; hinokitiol; neurodegeneration; prion protein