Prion Disorder Research Paper

The Elusive Prions and CJD: possible to treat?
Introduction to Prion Disease
Prion disease is an infectious neurodegenerative disease caused by a naturally occurring protein (PrPC) misfolding into an aberrant form
(PrPSC) which aggregates and destroys neuronal tissue. PrPSC was originally posited by Stanley Prusiner to be the sole causative moiety in prion disease (Prion Theory), however there is some evidence to suggest that unknown toxic intermediates, co-factors, and certain nucleic acids may have roles to play in its pathogenesis. In humans the diseases are named Creutzfeldt-Jakob Disease (CJD), GerstmannSträussler-Scheinker (GSS) syndrome, Fatal Familial Insomnia (FFI) and kuru. These conditions differ in aetiology, the cause
of PrP misfolding, but all are inexorably fatal.
As of yet there is no effective cure. The incubation times of prion diseases are usually long (years), but once clinically apparent are rapidly progressive.

Resistance to treatment & current approaches The disease-causing moiety, whether protein-only or not, is remarkably resistant to a myriad of physical , chemical and biological treatments and retains infectivity after:
• Irradiation with UV light
• Nucleases
• Hydrolysis
• Bleach
• Intense heat of 132*C for 30 minutes

Research Proposal: Lichens – natural born prion killers? Lichens are composite symbiotic organisms consisting of a fungus and a photosynthetic organism (usually algae or a cyanobacteria).

Current approaches to therapy :
•
Image showing the spongiform changes found in brains of prion disease-affected individuals.

CJD
Sporadic CJD (sCJD) – the seemingly ‘random’ conversion of normal

Inhibition of PrPC synthesis (prion replication requires the presence of normal cellular PrP as a template) • Stabilising PrPC conformation
• Enhancing PrPSC clearance
• Preventing PrPSC
replication

PrPC to pathogenic PrPSC, showing a mean clinical presentation age of
55-60 years with a short duration of illness. Most common form of CJD, comprising 85% of cases. Rare; incidence of 1 case per million people per year.
Recently (2011) a paper was published by Christopher J. Johnson et al who discovered species of lichen that effectively degrade PrPC and PrPSC in vitro.
By mixing infected and control brain homogenates with lichen extracts, they showed significantly reduced immunoreactivity of the PrP protein when precipitated with a PrP-specific antibody. The authors further showed that the likely agent causing this degradation was a serine-protease.

Variant CJD (vCJD) – In the UK, in 1996, vCJD was described, caused by bovine spongiform encephalopathy (BSE) found in cattle. It was thought to be transmitted to humans through the consumption of affected meat.
The mean age of presentation is approximately 19-37 years, normally showing a longer duration of illness than sCJD.

Familial CJD – autosomal dominant PrP gene mutations leading to the increased propensity for PrPC to misfold into PrPSC. This form of CJD is inherited. Codon 129 of PRNP gene often affects the phenotype.

Iatrogenic CJD – transmitted by PrPSC-contaminated medical equipment. A notable instance in the UK regarding human growth hormone treatment in children, whereby the isolates used contained
PrPSC from affected individuals.
References
Adriano Aguzzi, Christina Sigurdson and Mathias Heikenwaelder. Molecular Mechanisms of Prion
Pathogenesis. Annual Review of Pathology: Mechanism of Disease, 2008. 3:11-40.
•
Adriano Aguzzi and Magdalini Polymenidou. Mammalian Prion Biology: One Century of Evolving
Concepts. Cell, 2004. Vol. 116. 313-327.
• Christopher J. Johnson1, James P. Bennett, Steven M. Biro, Juan Camilo Duque-Velasquez,
• Cynthia M. Rodriguez, Richard A. Bessen, Tonie E. Rocke. Degradation of the Disease-Associated Prion
Protein by a Serine Protease from Lichens. PloS One, 2011. Vol 6 Issue 5.
•

Immunoblots showing PrP immunoreactivity after treatment with various lichen species’ extracts on infected deer, hamster and uninfected hamster brain homogenates.
Graph showing the survival of PrP-knockout mice and controls when inoculated with infectious PrPSC.

Why focus on treatment?

Although prion disease has a low incidence, it has a high profile especially after impressive media coverage of the BSE outbreak and is always fatal. Focussing on diagnostics without an effective treatment strategy is counterproductive, as improving the diagnosis of a currently incurable and fatal disease offers no clinical benefit. Proposal: In vivo administration of species-specific lichen extracts on prion-diseased brains to assess whether intracellular/membranebound PrP can be degraded to prevent replication of PrPSC in order to halt or reverse the clinical manifestations of prion disease.
Considerations such as the physiological effects of PrP depletion on the host, and side effects the lichen extracts may have on live neural tissue will be taken. The hypothesis is that under experimental conditions, lichen extracts administered in vivo and ex vivo (cultured neurons) will degrade prions. Using lichen extracts could also be used to sterilise medical equipment used with prion-diseased individuals.