UCL Dementia


Prion Diseases: Cracking the Enigma

As well as paving the way to new therapeutics, a better understanding of prion infections has implications for other neurodegenerative diseases. 

Prions, infectious protein particles, cause a range of degenerative brain diseases, including Creutzfeld-Jakob disease. In common with other neurodegenerative conditions, prion infections are characterised by the build up of abnormal protein aggregates. Understanding how such aggregates contribute to disease is a challenge across neurodegeneration. The work of Professor John Collinge and colleagues on the mechanisms of prion toxicity may therefore hold important lessons beyond prion disease. 

The infectious agent in prion diseases is a misfolded version of a cellular protein. This misfolded form, known as PrPSc, catalyses the conversion of the normal cellular protein, PrPC, into more copies of itself, which accumulate into protein aggregates. However, although this ultimately kills the cell, it is far from certain that the aggregates themselves are actually most damaging to the cell - a phenomenon common across neurodegenerative conditions. 

Several key features of prion infection require explanation. For example, prion infections show long incubation periods - decades in humans - but when clinical decline begins, it is extremely rapid, with death occurring within months. There is also no obvious link between levels of PrPSc build up and symptoms, and PrPSc is not toxic to cells unless they also express PrPC. 

These and other findings led Professor Collinge to propose a model in which infectivity and toxicity are dissociated. PrPSc is the agent responsible for transmission, but some other state - perhaps an intermediate in the transition from PrPC to PrPSc - is the neurotoxic agent. Studies of experimental infections in mice provided good evidence in support of this idea. 

The model implies that PrPSc is not itself toxic but causes harm through its effects on PrPC. Hence, maintaining PrPC in its native state should prevent PrPSc from exerting its harmful effects. This is the basis of therapeutic interventions being developed by Professor Collinge's laboratory (see page 14). More generally, the results add to a growing body of evidence that the characteristic large-scale aggregates seen in neurodegenerative conditions may not necessarily be the critical toxic entities.