How do prions work? November 21, 2006Posted by Hegemony in Health, Science.
Prion diseases operate differently than any other class of disease we are currently aware of. It is reliant on mutated forms of a common mammalian protein known as prion protein (PrPc). PrPc is highly homologous among mammals. In humans this protein is expressed in the central nervous system as well as in leukocytes and the gut. Common diseases known to be prion in nature include kuru, scrapie, Creutzfeldt–Jacob disease (CJD), Bovine Spongiform Encephalopathy (BSE/”mad cow”), and Gerstmann Straussler Scheinker (GSS) disease. Prion diseases are unique also in that there are three known ways for one to contract them: infectious, inherited, and sporadic.
A modified prion protein (PrPsc) has properties very different from those of the unmodified PrPc. PrPsc is highly resistant to the enzymatic degradation of the ubiquitin-proteasome system causing them to build up. This is a result of the changes in the secondary structure of PrPc, that is PrPsc has many areas of alpha helixes converted to beta sheets. These proteins build up in the brain causing cell death.
When a PrPsc molecule in introduced into a healthy animal it causes conformational changes in the healthy PrPc forms of the protein. This process is known as “Pruisner’s Theory”. This theory is evidenced by the tendency of aggregates to resemble the primary structure of the PrPc of a particular organism.
Recent studies have hinted that PrPsc aggregates are not necessary for prion-related neurotoxicity. If proteins are non-functional they are tagged by ubiquitin and degraded in a proteasome. This goes for PrPc as well. It has been discovered that if the ubiquitin-proteasome is inhibited, misfolded PrPc will build up in the cytosol and cause classic prion-related neurotoxicity. These PrPc proteins will aggregate in the cytosol and cannot be cleared by reinitializing the ubiquitin-proteasome system.
There are several findings in mouse studies that must be taken into consideration when thinking about the role of PrPsc in disease. It cannot cause disease when no PrPc is present. In a study mice with out the PrP gene (prpn) the PrPsc was unable to cause disease. Mice with truncated prpn producing non-functional PrP have high levels of cytosolic PrP and have massive neuronal loss. Older mice can spontaneously develop these symptoms, presumably sporadically. If PrPc production is inhibited in early PrPsc infection symptoms will not develop. The concentration of PrPsc does not seem to have an effect on the severity of the disease.
The new research raises many questions about the role of PrPc in relation to PrPsc exposure. It seems clear that PrPsc converts PrPc to the highly toxic form. However, it also seems clear that PrP itself can contribute to disease if the ubiquitin-proteasome system is not working properly.
It is put forth by researchers that the introduction of PrPsc may not be the determining factor in the development of neurodegenerative symptoms. This could be caused by a defect in the processing or metabolism of PrPc, or in the prpn gene itself. They state that an exogeneous form of PrPsc may initiate the events leading to the build up of PrPc in the cytosol and that this PrPc may fuel the further accumulation of PrPsc aggregates. This process may actually explain infectious, inherited, and sporadic prion disorders.