Prion Diseases: Are Researchers Finally Close to Uncovering a Cure?

Prion diseases are no laughing matter, although it might have seemed that way if you were a visitor on the island of Papua New Guinea in the 1950’s. It was here that members of the Fore tribe were suffering from what they had dubbed the “laughing sickness” due to the strange uncontrollable bursts of laughter that accompanied the debilitating shivering that struck it’s victims. The source of the disease, which came to be known as kuru, was found to be transmitted through ingestion of brain tissue during cannibalistic burial ceremonies. Ingestion of the diseased victims brain tissues exposed tribe members to a structurally altered form of the normally expressed cellular prion protein (PrP) which could react with healthy forms of the proteins in their brains, perpetuating further structural transformations.

There are a number of diseases spread in this manner, termed transmissible spongiform encephalopathies (TSE). All TSE's, which include the well-known mad cow disease (Creutzfeldt-Jakob disease), are inevitably fatal and lead to neurodegeneration, often mediated through pathologic neuroinflammation. The inflammation seems to be primarily due to the robust activation of microglial cells (Yang et al., 2008). Microglial cells are akin to the brain’s garbage trucks, constantly collecting cellular debris from the extracellular environment. This behavior coincidentally makes them especially fit for detecting the presence of extracellular pathogens as well.

Before a cure can be developed, researchers must first uncover the cellular mechanisms underlying the microglial-medated pathologic neuroinflammation observed in the victims of TSE. PrP106-126 is the region of the PrP protein that has been shown to mediate inflammatory and pathologic signaling following structural alteration. A recent study was able to use this peptide to identify many of the proteins and signaling molecules, thus potentially uncovering future targets for pharmaceutical therapies.


The study found that when rat microglia cells were treated with PrP106-126, proinflammatory cytokine levels were significantly increased. Cytokines are small signaling molecules that can be released from one cell and bind to a receptor in another to induce a specific response. In the case of microglia and proinflammatory cytokines, microglia that come into contact with a pathogen whose clearance would be best mediated through an inflammatory response will release cytokines that bind to receptors on other types of immune cells. These cells can then carry out cell-type specific activities that initiate the inflammatory response necessary to clear the detected pathogen.

The inflammatory cytokines that were released from microglia in response to PrP106-126 included IL-1B, IL-6, TNF-a, iNOS. While the individual activities carried out by each of these cytokines differ slightly, overall they all are important inflammatory mediators. The observed microglial activation was specific to PrP106-126 treatment, since no response was seen when a scrambled nonfunctional version of the peptide (ScrPrP) was used as the treatment or in control cells not treated with any peptide.

Cellular response to extracellular signals involves successive communication between several different signaling molecule. One of the signaling molecules important in producing the proinflammatory cytokine release observed in the microglial cultures is Nuclear factor-kappa B (NF-kB). NF-kB is an inflammatory regulator protein whose activity is normally inhibited by larger protein complexes in the cytoplasm of the cell. However, upon receipt of the proper signals, which could include proinflammatory signaling molecules, bacterial proteins, and viral infections, NF-kB is released from repressive control thus signaling it's activation. Once activated, NF-kB is able to leave the cytoplasm and enter the nucleus where it can bind to specific regions of the DNA to increase the production of the pro-inflammatory cytokines needed to induce the inflammatory response.

When microglial cultures were pre-treated with NF-kB inhibitors, all inflammatory cytokine release was attenuated. Thus, the key conclusion of this study is that the PrP106-126 induced upregulation of inflammatory cytokines is dependent upon NF-kB. With regards to prion diseases, previous studies have shown PrP106-126 can activate NF-kB by interacting with a cell receptor called p75NTR that is widely expressed in neurons and glia throughout the brain (Bai et al., 2008; Cragnolini & Friedman, 2008). Thus, when you put the pieces of the puzzle together, it appears PrP106-126 can act through p75NTR to upregulate NF-kB, triggering the inflammatory responses seen in the brains of those suffering from prion disorders.

Thus, there are several potential targets for therapies directed against TSE's. Microglial p75NTR or NF-kB activation would likely be the best places to begin search efforts, as these are what initiate the entire cascade leading to neurodegeneration and eventual death. However, other studies have also suggested it might be possible to target the PrP106-126 signaling region itself, through conformation-specific antibodies (Perchiacca et al., 2011). These recent breakthroughs suggest a treatment for TSE's could finally be in the near future.

Primary Article

Lu, Y., Liu, A., Zhou, X., Kouadir, M., Zhao, W., Zhang, S., Yin, X., Lifent, Y. & Zao, D. (2011). Prion peptide PrP106-126 induces inducible nitric oxide synthase and proinflammatory cytokine gene expression through the activation of NF-kB in macrophage cells.

Additional resources

Bai, Y., Li, Q., Yang, J., Zhou, X., Yin, X., Zhao, D. (2008). p75(NTR) activation of NF-kappaB is involved in PrP106-126-induced apoptosis in mouse neuroplastoma cells. Neurosci Res. 62(1), 9-14.

Cragnolini, A. & Friedman, W. (2008). The function of p75NTR in glia. Trends in Neuroscience. 31(2), 99-104.

Oerchiacca, J., Ladiwala, A., Bhattacharya, M. & Tessier, P. (2011). Structure-based design of conformation- and sequence-specific antibodies against amyloid B. PNAS. [In Press].

Yang, L., Zhou, X., Yang, J., Yin, X., Han, L., Zhao, D. (2008). Aspirin inhibits cytotoxicity of prion protein PrP106-126 to neuronal cells associated with microglial activation in vitro. J Neuroimmunol. 199(1-2), 10-17.