title: HIF-1α-induced β-catenin activation prevents prion-mediated neurotoxicity.
abstract: Previous studies have shown that hypoxic preconditioning attenuates prion-mediated neurotoxicity by upregulating hypoxia inducible factor-1α (HIF-1α). However, the mechanisms behind the HIF-1α-mediated neuroprotective effects in neurodegenerative disorders, including prion diseases, are unclear. It is well known that HIF-1α regulates Wnt/β-catenin signaling and that β-catenin protects neurons against misfolded protein-mediated disorders, including Alzheimer's and Parkinson's disease by preventing mitochondrial malfunction. Thus, we hypothesized that the mechanisms responsible for HIF-1α-mediated neuroprotection are associated with β-catenin activation induced by the regulation of mitochondrial function. We used the SH-SY5Y human neuroblastoma cell line and treated the cells with melatonin and then exposed them to the prion protein, PrP, or the β-catenin inhibitor, ICG-001. TUNEL assay was used to measure apoptosis. β-catenin expression measured by western blot analysis. The results revealed that HIF-1α prevented prion protein (PrP) (106-126)-induced neurotoxicity by activating β-catenin. Moreover, HIF-1α-induced β-catenin activation prevented the PrP (106-126)-induced mitochondrial damage under hypoxic conditions, as evidenced by the higher mitochondrial transmembrane potential values in the cells exposed to hypoxic conditions. These results indicate that the regulation of β-catenin activation by HIF-1α may be a therapeutic strategy for prion-mediated disorders.
authors.affiliation: Bio-Safety Research Institute, College of Veterinary Medicine, Chonbuk National University, Jeonju, Jeonbuk 561-756, Republic of Korea.
authors.forename: Jae-Kyo
authors.initials: JK
authors.lastname: Jeong
authors.forename: Sang-Youel
authors.initials: SY
authors.lastname: Park
mesh_terms: D017209:Apoptosis; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D008550:Melatonin / Q000009:adverse effects; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000009:adverse effects*; D017096:Prion Diseases / Q000235:genetics / Q000628:therapy; D011328:Prions / Q000009:adverse effects*; D011744:Pyrimidinones / Q000494:pharmacology; D015854:Up-Regulation; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; C495270:CTNNB1 protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C492448:ICG 001; D010446:Peptide Fragments; D011328:Prions; D011744:Pyrimidinones; D051176:beta Catenin; C082632:prion protein (106-126); D008550:Melatonin