Post by Elisa Guma
What's the science?
Prion diseases are progressive neurodegenerative diseases for which no effective treatment is available. They are associated with a buildup of misfolded forms of naturally occurring proteins in the brain, known as prion proteins. Once formed, prion proteins can convert other normal proteins into an abnormal form, causing a chain reaction, leading to accumulation of prions, neuronal death, and progressive cognitive decline. Neuroinflammation is known to be associated with prion diseases, however, the interaction between the immune system and prion accumulation in prion diseases remains unclear. This week in Brain, Ishibashi and colleagues used in vivo and ex vivo prion disease models to understand the protective role of type I interferon (I-IFN), part of the body’s innate immune response, against prion disease.
How did they do it?
The authors first investigated expression of various inflammatory signaling genes in a prion-infected cell culture (ex vivo model). Next, the authors investigated the potential anti-prion effect of I-IFNs (alpha and beta interferons) in the cell culture model, first by administering the I-IFNs, and then by administering Poly I:C (which activates the innate immune system via I-IFN induction) to see if this could rescue the prion infection. They then investigated the potential protective property of IFN in mice that were prion infected by selectively expressing the IFN-beta gene in the brains of these mice and then measuring the prion proteins expressed in their brains. The authors wanted to confirm that prion suppression was due specifically to IFN signaling, therefore they generated a cell line that did not express IFN receptors and examined prion expression. They also infected normal (wild-type) mice, and mice lacking IFN receptors, and monitored prion protein expression and gliosis in the brain.
The authors also investigated the effects of RO8191, a compound known to bind to the I-IFN receptor, and increase IFN related gene expression and signaling. They first administered RO8191 to cells, and measured prion protein levels. They then tested the efficacy of R08191 treatment in mice, administering treatment from the time of prion infection until death (3x/week). Lastly, the authors tested the blood-brain-barrier (a protective layer between brain tissue and blood vessels connected to the rest of the body) permeability of RO8191 by measuring RO8191 concentration in the brain and spleens of the treated mice.
What did they find?
The authors found that prion infection decreased gene expression related to inflammatory signaling, including the I-IFN related gene. Next, they found that treating the prion infected cell line with IFN-beta (and alpha to a lesser extent), or Poly I:C (to stimulate IFN production) significantly reduced the number of prion proteins in the cell line. Introducing the IFN-beta into the brain of prion infected mice was also successful at reducing prion protein expression. The authors also observed that removal of IFN receptor genes significantly increased prion protein levels in cell lines, whereas and reintroduction of the IFN gene to these cells made them less susceptible to prion infection. Similarly, mice whose IFN genes had been knocked out were more susceptible to the prion infection - their lifespan was shortened, they had higher levels of prions in their brain and spleen and higher levels of gliosis (microglia and astrocytes) in their brain.
Next, the authors found that pre-treating prion infected cells and mice with R08191 decreased prion protein levels in the cells and in the brain and spleens of mice by at least 50%. Gliosis was also reduced in many brain regions including the cortex, thalamus and pons. Finally, the authors found that RO8191 had high blood-brain-barrier permeability, suggesting that it may reach and act on the brain, in addition to peripheral tissues.
What's the impact?
This study provides evidence that interferons may play a protective role against prion proteins in both cell lines and mice. Additionally, treatment with the novel small molecule RO8191, known to bind to the I-IFN receptor, was successful at reducing prion protein expression, making it a candidate for treatment. A better understanding of the role of the innate immune system in prion disease may provide ideas for novel therapeutic agents.
Ishibashi et al. Type I interferon protects neurons from prions in in vivo models. Brain (2019). Access the original scientific publication here.