Hypoxia-inducible factor-1 α regulates prion protein expression to protect against neuron cell damage.
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.
Center for Healthcare Technology Development, Korea Zoonoses Research Institute, College of Veterinary Medicine, Chonbuk National University, Jeonju, Jeonbuk, South Korea.
Jae-Kyo
JK
Jeong
Jae-Suk
JS
Seo
Myung-Hee
MH
Moon
You-Jin
YJ
Lee
Jae-Won
JW
Seol
Sang-Youel
SY
Park
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D002534:Hypoxia, Brain / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018621:PrPC Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000633:toxicity; D017096:Prion Diseases / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018621:PrPC Proteins