A Kiss of a Prion: New Implications for Oral Transmissibility

The Journal of Infectious Diseases (Impact Factor: 6). 06/2010; 201(11):1615-6. DOI: 10.1086/652458
Source: PubMed
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Available from: Bianca Da Costa Dias, Jun 12, 2014
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    ABSTRACT: The 37-kDa/67 kDa laminin receptor (LRP/LR) represents a multifunctional protein. It is a receptor for viruses such as Dengue viruses, Alphaviruses and Adeno-associated viruses (AAV), as well as the cellular prion protein (PrPc) and infectious prions. Furthermore, the 37-kDa/67-kDa LRP/LR plays fundamental roles in basic cell biological processes such as cell adhesion and cell growth and acts as a key player in metastatic cancer, affecting invasion, adhesion and apoptotic processes. This review gives fundamental insights into basic cellular processes affected by LRP/LR including signal transduction and cell cycle progression and focuses on pathophysiological implications of the interaction of prion proteins, laminin, viruses and other ligands with LRP/LR affecting the development of highly-prevalent diseases such as cancer, neurodegenerative diseases such as prion disorders and Alzheimer's disease as well as viral infections. Molecular tools such as LRP/LR specific antibodies and siRNAs targeting LRP expression as possible alternative therapeutics for the treatment of neurodegenerative diseases, metastatic cancer and viral infections are emphasized.
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    ABSTRACT: Enterocytes, a major cell population of the intestinal epithelium, represent one possible barrier to the entry of prions after oral exposure. We established a cell culture system employing enterocytes from different species to study alimentary prion interaction with the 37-kDa/67-kDa laminin receptor LRP/LR. Human, bovine, porcine, ovine, and cervid enterocytes were cocultured with brain homogenates from cervid, sheep, and cattle suffering from chronic wasting disease (CWD), scrapie, and bovine spongiform encephalopathy (BSE), respectively. PrP(CWD), ovine PrP(Sc), and PrP(BSE) all colocalized with LRP/LR on human enterocytes. PrP(CWD) failed to colocalize with LRP/LR on bovine, porcine, and ovine enterocytes. Ovine PrP(Sc) colocalized with the receptor on bovine enterocytes, but failed to colocalize with LRP/LR on cervid and porcine enterocytes. PrP(BSE) failed to colocalize with the receptor on cervid and ovine enterocytes. These data suggest possible oral transmissibility of CWD and sheep scrapie to humans and may confirm the oral transmissibility of BSE to humans, resulting in zoonotic variant Creutzfeldt-Jakob disease. CWD might not be transmissible to cattle, pigs, and sheep. Sheep scrapie might have caused BSE, but may not cause transmissible spongiform encephalopathy in cervids and pigs. BSE may not be transmissible to cervids. Our data recommend the enterocyte model system for further investigations of the intestinal pathophysiology of alimentary prion infections.
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    ABSTRACT: Neurodegenerative diseases are caused by proteinaceous aggregates, usually consisting of misfolded proteins which are often typified by a high proportion of β-sheets, which accumulate in the Central Nervous System. These diseases, including Morbus Alzheimer, Parkinson disease and Transmissible Spongiform Encephalopathies (TSEs)--also termed prion disorders--afflict a substantial proportion of the human population and as such the etiology and pathogenesis of these diseases has been the focus of mounting research. Although many of these diseases arise from genetic mutations or are sporadic in nature, the possible horizontal transmissibility of neurodegenerative diseases poses a great threat to population health. In this article we discuss recent studies which suggest that the "non-transmissible" status bestowed upon Alzheimer and Parkinson diseases may need to be revised as these diseases have been successfully induced through tissue transplants. Furthermore, we highlight the importance of investigating the "natural" mechanism of prion transmission including peroral and perenteral transmission, proposed routes of gastrointestinal uptake and neuroinvasion of ingested infectious prion proteins. We examine the multitude of factors which may influence oral transmissibility and discuss the zoonotic threats which Chronic Wasting Disease (CWD), Bovine Spongiform Encephalopathy (BSE) and Scrapie may pose resulting in vCJD or related disorders. In addition, we suggest that the 37 kDa/67 kDa laminin receptor on the cell surface of enterocytes, a major cell population in the intestine, may play an important role in the intestinal pathophysiology of alimentary prion infections.
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