From "Molecular neurology of prion disease" by J Collinge:

The nature of the transmissible agent has been a subject of intense and heated debate for many years. The initial assumption was that it must be viral, but no virus could ever be identified and the transmissible agent was resistant to treatments which inactivate nucleic acids (such as ultraviolet radiation or treatment with nucleases).

These remarkable findings led to suggestions in 1966 by Tikvar Alper and others that the transmissible agent may be devoid of nucleic acid and led John Griffith to suggest in 1967 that the transmissible agent may in fact be composed entirely of protein.

In his remarkable letter to Nature, he proposed three hypothetical mechanisms for propagation of such an agent, one of which closely mirrors current thinking; indeed his model also predicted the existence of distinct strains of agent. Needless to say, such a proposal met with great scepticism at the time, in what was the heyday of the “central dogma” of biology: that DNA encodes RNA that in turn encodes protein.

More than a decade later this revolutionary proposal was lent biochemical credibility by intensive purification studies allied with laborious rodent bioassay. Progressive enrichment of brain homogenates for infectivity resulted in the isolation of a protease resistant glycoprotein, designated the prion protein (PrP) by Prusiner and co-workers in 1982. This protein was the major constituent of infective fractions and was found to accumulate in affected brains and sometimes to form amyloid deposits. The term prion (from proteinaceous infectious particle) was proposed to distinguish the infectious pathogen from viruses or viroids. Prions were defined as “small proteinaceous infectious particles that resist inactivation by procedures which modify nucleic acids”.

Clinical neurology and neurogenetics have played a major role in the evolution of our understanding of the pathobiology of prion disease. Study of the various forms of human prion disease has been crucial, notably the recognition that the familial forms of the human diseases – already known to be transmissible to laboratory animals by inoculation – are in fact autosomal dominant inherited conditions associated with coding mutations in the gene encoding PrPC (designated PRNP) The very strong genetic linkage and high or complete penetrance of some such mutations left no need to propose any external infectious agent and argued strongly for what had become known as the “protein-only” hypothesis of prion propagation.

In common with other pathogens, distinct naturally occurring isolates or strains of prions are observed.

These are distinct prion isolates that maintain distinct characteristics when serially passaged in susceptible animals (can be isolated and cloned)

They can be distinguished by differences in a heritable phenotype, pertaining to incubation period, clinical signs of disease (histopathological lesion profiles), tissue tropism, and host range.

On the molecular or biochemical level, they can sometimes be defined by the differences in PrP proteolytic fragment sizes and glycosylation patterns (PrP glycoform ratios). How these ratios are maintained is not yet known.

The recent cryo-EM structures showed that prion fibrils from distinct prion strains are built from distinctly folded chains of PrP, which revealed the structural basis of prion strains (see below).

Although much progress has been made on understanding the etiological agent of prion disease, the relationship between the strain-specific properties of PrPSc and the resulting phenotype of disease in animals is poorly understood.

The recent prion structures solved by cryo-electron microscopy (cryo-EM) at near-atomic resolution showed that prion fibrils from distinct rodent prion strains are built from distinctly folded chains of PrP. Those PrP chains, the basic building blocks of prion fibrils, are arranged in a parallel manner, forming something of a twisted ribbon, with each PrP forming a single rung spanning the full width of that ribbon. This type of arrangement is characteristic for so-called amyloid fibrils. Thus, on the structural level, prion strain diversity relies on differences in the PrP fold within prion fibrils - strain-specific PrPSc conformations or structures. Strain-specific cellular cofactors may also contribute to prion strain diversity.