Review of Miyazawa's "Continuous Production of Prions after Infectious Particles Are Eliminated: Implications for Alzheimer's Disease"

The curious nature of Pruisner's Prion Hypothesis as one that challenged the Central Dogma of molecular biology and seems to contravene a number of Koch's postulates, as described in earlier posts, has led a number of researchers to seek alternative explanations for prion transmission and for the core agent of prion diseases.  In one such study, Miyazawa et. al. build on prior work by their co-author Manuelidis that showed an absence of detectable prions in material that was demonstrably infectious when injected into healthy brain tissue (Manuelidis 2007).

Miyazawa built on this anomaly to hypothesize that the formation of misfolded PrP proteins in a host may be, rather than progression and transmission of a disease agent itself (misfolded proteins), part of a pathological host response to a different infection (Miyazawa 2012).  Compellingly, the research team measured infectious titers from mice suffering from prion diseases at at different stages of progression and provide compelling evidence that prions are present in tissue that is no longer infectious (Id.).  Moreover, misfolded PrP proteins formed in brain tissue that had been exposed to "infected" misfolded PrP cells even after all misfolded PrP proteins had been removed (Id.).   These two points directly challenge the broadly accepted model of prion transmission that misfolded PrP proteins "teach" normal PrP proteins to misfold.

To summarize Miyazawa's work, the team exposed rate brain cells to infected PrP titers at both proliferating and arresting conditions and over different periods of time  in order to compare infectivity of the disease agents at various stages (Miyazawa 2012).  As described above, this led them to the interesting results that infective titers that did not contain actual prion proteins led to transmission of prion formation in the healthy tissue and, conversely, titers with high levels of prion proteins that had been treated in arresting conditions after significant time led to, in some cases, no infection (Id.).  Compellingly, issue was shown to be infectious in early stages of prion disease and even before the onset of prion disease symptoms (Miyazawa, 2012).  However, brain titers of very late-stage mice suffering from TSEs—and where large amounts of PRP^sc were present, did not transmit disease to mice injected with that brain material (Miyazawa, 2012).

The results indicate that the prion agent may well not be the infectious agent itself and, as Miyazawa theorizes, a third party agency, such as a virus, is the likely cause for the host response to fight that third party agent, which results in the misfolded PrP protein (Miyazwa 2012).  This is profoundly important from an epidemiological standpoint of how prion disease are transmitted.  Indeed, if transmission is not the result of misfolded proteins teaching native proteins to fold incorrectly, but rather of a virus causing a host immune reaction, the lure of treatment possibilities arise.

As a result, these authors could consider a study in which infected hosts or rats are treated with antivirals to see if those have any effect on the formation of the prions.  This could indicate that, if the virus was kept at bay, the immune system may not form prions as part of a bodily response.  In addition, the authors could consider a study in which immunosuppressant drugs may be provided to the host in order to see if disease progression could be halted on that front.  These types of future studies could lead to the development of prevention techniques or treatment options better suited to the true agent of prion diseases.

This figure taken from Miyazawa 2012.  It shows total PrP (light grey bars) and percent misfolded PrP (dark grey bars) at progressive times in each of three experiments.  Notably, titers with high levels of misfolded proteins later in the studies were less infectious than anticipated.

Article Reviewed:
Miyazawa, Kohtaro, T. Kipkorir, S. Tittman, L. Manuelidis, 2012.  Continuous production of prions after infectious particles are eliminated: Implications for Alzheimer’s disease.  PLoS One.  7(4): 1-8.

Other Works Cited

Manuelidis, Laura, Z. Yu, N. Barquero, and B. Mullins, 2007.  Cells infected with Scrapie and Creutzfeldt-Jakob disease agents produce intracellular 25-nm virus-like particles.  104(14): 1965-1970.