HIF-1 alpha-induced beta-catenin activation prevents prion-mediated neurotoxicity

作者：Jeong Jae Kyo; Park Sang Youel^*

来源：International Journal of Molecular Medicine, 2013, 32(4): 931-937.

DOI：10.3892/ijmm.2013.1457

• beta-catenin
• hypoxia
• hypoxia inducible factor-1 alpha
• mitochondrial dysfunction
• prion diseases

Previous studies have shown that hypoxic preconditioning attenuates prion-mediated neurotoxicity by upregulating hypoxia inducible factor-1 alpha (HIF-1 alpha). However, the mechanisms behind the HIF-1 alpha-mediated neuroprotective effects in neuro-degenerative disorders, including prion diseases, are unclear. It is well known that HIF-1 alpha regulates Wnt/beta-catenin signaling and that beta-catenin protects neurons against misfolded protein-mediated disorders, including Alzheimer%26apos;s and Parkinson%26apos;s disease by preventing mitochondrial malfunction. Thus, we hypothesized that the mechanisms responsible for HIF-1 alpha-mediated neuroprotection are associated with beta-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 beta-catenin inhibitor, ICG-001. TUNEL assay was used to measure apoptosis. beta-catenin expression measured by western blot analysis. The results revealed that HIF-1 alpha prevented prion protein (PrP) (106-126)-induced neurotoxicity by activating beta-catenin. Moreover, HIF-1 alpha-induced beta-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 beta-catenin activation by HIF-1 alpha may be a therapeutic strategy for prion-mediated disorders.

• 出版日期2013-10