Skip to main content
Article thumbnail
Location of Repository

Continuous Production of Prions after Infectious Particles Are Eliminated: Implications for Alzheimer’s Disease

By Kohtaro Miyazawa, Terry Kipkorir, Sarah Tittman and Laura Manuelidis

Abstract

Rat septal cells, induced to enter a terminal differentiation-like state by temperature shift, produce prion protein (PrP) levels 7x higher than their proliferative counterparts. Host PrP accumulates on the plasma membrane, newly elaborated nanotubes, and cell-to-cell junctions, important conduits for viral spread. To find if elevated PrP increased susceptibility to FU-CJD infection, we determined agent titers under both proliferating and arresting conditions. A short 5 day arrest and a prolonged 140 day arrest increased infectivity by 5x and 122x (>2 logs) respectively as compared to proliferating cells. Total PrP rapidly increased 7x and was even more elevated in proliferating cells that escaped chronic arrest conditions. Amyloid generating PrP (PrP-res), the “infectious prion” form, present at ∼100,000 copies per infectious particle, also increased proportionately by 140 days. However, when these highly infectious cells were switched back to proliferative conditions for 60 days, abundant PrP-res continued to be generated even though 4 logs of titer was lost. An identical 4 log loss was found with maximal PrP and PrP-res production in parallel cells under arresting conditions. While host PrP is essential for TSE agent spread and replication, excessive production of all forms of PrP can be inappropriately perpetuated by living cells, even after the initiating infectious agent is eliminated. Host PrP changes can start as a protective innate immune response that ultimately escapes control. A subset of other neurodegenerative and amyloid diseases, including non-transmissible AD, may be initiated by environmental infectious agents that are no longer present

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:3324552
Provided by: PubMed Central
Download PDF:
Sorry, we are unable to provide the full text but you may find it at the following location(s):
  • http://www.pubmedcentral.nih.g... (external link)
  • Suggested articles

    Citations

    1. (2007). A 25 nm Virion Is the Likely Cause of Transmissible Spongiform Encephalopathies.
    2. (2008). A rapid accurate culture assay for infectivity in transmissible encephalopathies.
    3. (2008). Absence of the cellular prion protein exacerbates and prolongs neuroinflammation in experimental autoimmune encephalomyelitis.
    4. (2009). Antimicrobial activity of human prion protein is mediated by its N-terminal region. PLoS ONE.7(4):
    5. (1994). Conditional immortalization of neuronal cells from postmitotic cultures and adult CNS.
    6. (2011). De novo generation of prion strains.
    7. (1994). Dementias, neurodegeneration, and viral mechanisms of disease from the perspective of human transmissible encephalopathies.
    8. (2008). Detection and characterization of proteinase K-sensitive disease-related prion protein with thermolysin.
    9. (2011). Endogenous Prion Protein Attenuates Experimentally Induced Colitis.
    10. (1997). Evolution of a strain of CJD that induces BSE-like plaques.
    11. (2011). Functional mechanisms of the cellular prion protein (PrP(C)) associated anti-HIV-1 properties. Cell Mol Life Sci.
    12. (2012). Genetic informational RNA is not required for recombinant prion infectivity.
    13. (2011). High CJD infectivity remains after prion protein is destroyed.
    14. (2005). In vitro generation of infectious scrapie prions.
    15. (1996). Infectivity and host responses in CreutzfeldtJakob Disease.
    16. (2011). Lower specific infectivity of protease-resistant prion protein generated in cell-free reactions.
    17. (2002). Microglia from Creutzfeldt-Jakob Disease-infected brains are infectious and show specific mRNA activation profiles
    18. (1991). Molecular biology of prion diseases.
    19. (2001). Neuroinvasion by a Creutzfeldt-Jakob disease agent in the absence of B cells and follicular dendritic cells.
    20. (2004). New molecular markers of early and progressive CJD brain infection.
    21. (2010). Nuclease resistant circular DNAs copurify with infectivity in scrapie and CJD.
    22. (1996). Prion protein (PrP) with amino-proximal deletions restoring susceptibility of PrP knockout mice to scrapie.
    23. (2010). Proliferative arrest of neural cells induces prion protein synthesis, nanotube formation, and cell-to-cell contacts.
    24. (2005). Reciprocal interference between specific CJD and scrapie agents in neural cell cultures.
    25. (2011). Replication and spread of CJD, kuru and scrapie in vivo and in cell culture.
    26. (2005). Stimulation of poliovirus RNA synthesis and virus maturation in a HeLa cellfree in vitro translation-RNA replication system by viral protein 3CDpro.
    27. (2009). Strain-specific viral properties of variant Creutzfeldt–Jakob Disease (vCJD) are encoded by the agent and not by host prion protein.
    28. (1989). Suggested links between different types of dementias: Creutzfeldt-Jakob disease, Alzheimer Disease, and retroviral CNS infections.
    29. (2004). Synthetic mammalian prions.
    30. (2009). The kuru infectious agent is a unique geographic isolate distinct from Creutzfeldt–Jakob disease and scrapie agents.
    31. (2004). Two Creutzfeldt-Jakob disease agents reproduce prion protein-independent identities in cell cultures.
    32. (2011). Ultra-efficient PrP(Sc) amplification highlights potentialities and pitfalls of PMCA technology.
    33. (2003). Unique inflammatory RNA profiles of microglia in Creutzfeldt-Jakob disease.
    34. (1978). Viremia in experimental Creutzfeldt-Jakob disease.

    To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.