GENERAL INTRODUCTION: PRION DISEASES

Introduction

Scrapie is the oldest known transmissible spongiform encephalopathy (TSE) and was first described in sheep in 1750 in a German book on agriculture although others implied that it has been known since Roman times.¹⁶⁹ Many theories existed about the cause of the disease; hereditary, sexually transmitted and/ or infectious but only in the 20^th century was it demonstrated that the scrapie agent was transmissible.

Major events leading to our current knowledge of scrapie occurred as follows:

• 1898: Description of the microscopic neuropathology and neuronal vacuolation notably of motor neurons in the spinal cord.¹⁷
• 1936: Scrapie shown to be an experimentally transmissible disease in sheep.³⁴
• 1936 to 1938: Iatrogenic scrapie occurred in hundreds of sheep in Great Britain through the use of louping-ill vaccine contaminated accidentally with scrapie agent from brains and spleens of sheep used for its manufacture. This was first reported at the Third International Congress for Microbiology⁷⁵ and subsequently published in 1946.⁷⁴ The transmissible nature of the scrapie agent was thus confirmed beyond reasonable doubt.
• 1957 to 1959: Zigas and Gajdusek reported the occurrence of kuru (trembling or shivering of the body, also known as the laughing death), a rare and unusual neurological disease in the Fore-speaking people of Papua New Guinea.²²¹ They believed this was propagated by endocannibalistic consumption of the whole bodies of dead relatives during funeral rites. The American veterinary pathologist W.J. Hadlow made the important pathological connection between scrapie of sheep and kuru of humans by observing that ‘the overall resemblance between kuru and scrapie is too impressive to be ignored’.⁸⁰ He went on to suggest the experimental transmission of kuru to a laboratory primate. This was subsequently achieved and was followed by successful transmission of human Creutzfeldt-Jakob disease (CJD) to primates, thus establishing that these rare human disorders were, like scrapie, transmissible spongiform encephalopathies (TSEs).
• 1961: Experimental transmission of scrapie to mice thus establishing a model system in which the disease, and the agent that caused it, could be studied in the laboratory²⁶
• 1966 to 1967: Report of the very small size of the scrapie agent, its almost complete resistance to destruction by massive germicidal doses of ionizing radiation supporting the view that the agent may have a mode of replication independent of the integrity of a nucleic acid moiety.^{4, 5}
• 1979: Report of the scrapie replication site hypothesis⁴⁵ and the results of studies on the genetics of scrapie in sheep and mice.⁴⁴ The latter report showed that murine genes influenced the phenotype of scrapie, notably its incubation period and lesion profile, when a small number of important factors were controlled. This work was the basis for identifying and distinguishing strains of scrapie agent and led to further opportunities to study the pathogenesis of scrapie notably by Bruce, Dickinson, Fraser and Kimberlin. The scrapie strain typing methods were to become vitally important after the discovery of bovine spongiform encephalopathy (see Bovine spongiform encephalopathy).
• 1979, 1980 and 1982: Reports on the tissue distribution of scrapie infectivity in goats and Suffolk sheep and in some other breeds of sheep with natural scrapie, including during the incubation period of Suffolk sheep from high scrapie-risk families^82-84
• 1982: Establishment of the prion definition (small, proteinaceous infectious particles that resist inactivation by procedures that modify nucleic acids) and prion hypothesis.¹⁵⁷
• 1990: Description of prion protein polymorphisms at position 171 associated with incubation control of scrapie in sheep.⁶² Additional polymorphisms were later identified at positions 136 and 154; all associated with scrapie susceptibility in sheep. This formed the basis for scrapie eradication by genotype selection in various countries.
• 2003: Report of a new type of scrapie in Norway, Nor98,¹⁶ which was subsequently found in other countries, including those considered free from scrapie. This disease was later termed ‘atypical scrapie’ to distinguish it from ‘classical scrapie’ that has been known for centuries. Retrospective studies confirmed atypical scrapie in archived sheep material from the 1970s and 1980s,^{27, 213} which suggests that it is not a new disease.

Substantial epidemiological studies have failed to reveal a connection between CJD in humans and scrapie; these were summarized by the European Food Safety Authority in 2011.⁴⁶ Subsequently, it has been shown that some classical scrapie isolates can be transmitted to transgenic mice carrying the human prion protein gene and reproduce characteristics of a disease on second passage with similarities to sporadic CJD.²⁵ Whilst this may indicate that some isolates of the scrapie...