Center for Healthcare Technology Development, Korea Zoonoses Research Institute, College of Veterinary Medicine, Chonbuk National University, Jeonju, Jeonbuk, South Korea.
Neurobiol Aging. 2012 May;33(5):1006.e1-10. doi: 10.1016/j.neurobiolaging.2011.09.037. Epub 2011 Oct 28.
The human prion protein fragment, PrP (106-126), may contain a majority of the pathological features associated with the infectious scrapie isoform of PrP, known as PrP(Sc). Based on our previous findings that hypoxia protects neuronal cells from PrP (106-126)-induced apoptosis and increases cellular prion protein (PrP(C)) expression, we hypothesized that hypoxia-related genes, including hypoxia-inducible factor-1 alpha (HIF-1α), may regulate PrP(C) expression and that these genes may be involved in prion-related neurodegenerative diseases. Hypoxic conditions are known to elicit cellular responses designed to improve cell survival through adaptive processes. Under normoxic conditions, a deferoxamine-mediated elevation of HIF-1α produced the same effect as hypoxia-inhibited neuron cell death. However, under hypoxic conditions, doxorubicin-suppressed HIF-1α attenuated the inhibitory effect on neuron cell death mediated by PrP (106-126). Knock-down of HIF-1α using lentiviral short hairpin (sh) RNA-induced downregulation of PrP(C) mRNA and protein expression under hypoxic conditions, and sensitized neuron cells to prion peptide-mediated cell death even in hypoxic conditions. In PrP(C) knockout hippocampal neuron cells, hypoxia increased the HIF-1α protein but the cells did not display the inhibitory effect of prion peptide-induced neuron cell death. Adenoviruses expressing the full length Prnp gene (Ad-Prnp) were utilized for overexpression of the Prnp gene in PrP(C) knockout hippocampal neuron cells. Adenoviral transfection of PrP(C) knockout cells with Prnp resulted in the inhibition of prion peptide-mediated cell death in these cells. This is the first report demonstrating that expression of normal PrP(C) is regulated by HIF-1α, and PrP(C) overexpression induced by hypoxia plays a pivotal role in hypoxic inhibition of prion peptide-induced neuron cell death. These results suggest that hypoxia-related genes, including HIF-1α, may be involved in the pathogenesis of prion-related diseases and as such may be a therapeutic target for prion-related neurodegenerative diseases.
人类朊病毒蛋白片段，PrP（106-126），可能包含与传染性瘙痒病朊病毒形式的 PrP（称为 PrP（Sc））相关的大多数病理特征。基于我们之前的发现，缺氧可保护神经元细胞免受 PrP（106-126）诱导的凋亡，并增加细胞朊病毒蛋白（PrP（C））的表达，我们假设缺氧相关基因，包括缺氧诱导因子-1α（HIF-1α），可能调节 PrP（C）的表达，并且这些基因可能与朊病毒相关的神经退行性疾病有关。缺氧条件已知会引起细胞反应，旨在通过适应过程提高细胞存活率。在常氧条件下，通过去铁胺介导的 HIF-1α 的升高产生与缺氧抑制神经元细胞死亡相同的效果。然而，在缺氧条件下，阿霉素抑制的 HIF-1α 减弱了 PrP（106-126）介导的对神经元细胞死亡的抑制作用。在缺氧条件下，使用慢病毒短发夹（sh）RNA 敲低 HIF-1α 导致 PrP（C）mRNA 和蛋白质表达的下调，并使神经元细胞对朊病毒肽介导的细胞死亡敏感，即使在缺氧条件下也是如此。在 PrP（C）敲除海马神经元细胞中，缺氧增加了 HIF-1α 蛋白，但细胞没有显示出抑制朊病毒肽诱导的神经元细胞死亡的作用。表达全长 Prnp 基因的腺病毒（Ad-Prnp）用于在 PrP（C）敲除海马神经元细胞中过表达 Prnp 基因。腺病毒转染 PrP（C）敲除细胞与 Prnp 导致这些细胞中朊病毒肽介导的细胞死亡的抑制。这是第一个表明正常 PrP（C）的表达受 HIF-1α 调节的报告，并且缺氧诱导的 PrP（C）过表达在缺氧抑制朊病毒肽诱导的神经元细胞死亡中起着关键作用。这些结果表明，缺氧相关基因，包括 HIF-1α，可能与朊病毒相关疾病的发病机制有关，因此可能是朊病毒相关神经退行性疾病的治疗靶点。
