Abstract
BackgroundThe physiological function of the cellular prion protein (PrPC) remains unknown. However, PrPC has been reported to possess a cytoprotective activity that prevents death of neurons and other cells after a toxic stimulus. To explore this effect further, we attempted to reproduce several of the assays in which a protective activity of PrP had been previously demonstrated in mammalian cells.ResultsIn the first set of experiments, we found that PrP over-expression had a minimal effect on the death of MCF-7 breast carcinoma cells treated with TNF-α and Prn-p0/0 immortalized hippocampal neurons (HpL3-4 cells) subjected to serum deprivation. In the second set of assays, we observed only a small difference in viability between cerebellar granule neurons cultured from PrP-null and control mice in response to activation of endogenous or exogenous Bax.ConclusionTaken together, our results suggest either that cytoprotection is not a physiologically relevant activity of PrPC, or that PrPC-dependent protective pathways operative in vivo are not adequately modeled by these cell culture systems. We suggest that cell systems capable of mimicking the neurotoxic effects produced in transgenic mice by N-terminally deleted forms of PrP or Doppel may represent more useful tools for analyzing the cytoprotective function of PrPC.
Highlights
The physiological function of the cellular prion protein (PrPC) remains unknown
Expression of PrP in MCF-7 cells weakly suppresses death induced by tumor necrosis factor-α (TNF-α) To test the observation that cellular isoform of PrP (PrPC) rescues MCF-7 human breast carcinoma cells from TNF-α-mediated cell death [31], we first determined the sensitivity of MCF-7 cells to TNF-α treatment using two different assays: MTT dye reduction, and flow cytometry after propidium iodide staining to measure the proportion of cells with sub-2n DNA content
We examined the effect of PrP expression on the viability of MCF-7 breast carcinoma cells treated with TNF-α, HpL3-4 immortalized hippocampal neurons deprived of serum, and cultured cerebellar granule neurons induced to undergo two kinds of Baxdependent apoptosis
Summary
The physiological function of the cellular prion protein (PrPC) remains unknown. PrPC has been reported to possess a cytoprotective activity that prevents death of neurons and other cells after a toxic stimulus. To explore this effect further, we attempted to reproduce several of the assays in which a protective activity of PrP had been previously demonstrated in mammalian cells. While the properties of PrPSc and its role in the disease process have been extensively characterized, the normal physiological function of PrPC has yet to be resolved. Determining the normal function of PrPC will likely provide important insight into the neurotoxic mechanisms underlying prion diseases
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