Open Vets. 2020; 1: 1-14 Review Article David B. Adams* Prion Evolvability and the Hazard of Atypical Scrapie in Small Ruminants https://doi.org/10.1515/ovs-2020-0001 received April 22, 2019; accepted August 20, 2019 1 Introduction The discipline of evolutionary biology provides special Abstract: Observations on strain behaviour and direct insights into the natural history of disease and is vital demonstrations of natural selection establish that the to the practice of medicine and public health across scrapie agent and prions in general are able to evolve. all species [1, 2]. Evolutionary biology has been applied Accordingly, it is conceivable that atypical non-conta- to scrapie disease in sheep [3] where it showed that the gious scrapie in sheep and goats can transform to classi- scrapie agent, a prion or ‘proteinaceous infectious agent’ cal contagious scrapie under particular circumstances. In [4], and prions in general possess the functions of varia- consequence, atypical scrapie can be regarded as a latent tion, reproduction and heritability that drive evolution [5]. hazard that warrants comprehensive risk assessment Prions are thus endowed with evolvability or the capac- and biosecurity preparedness planning. Evidence for this ity for generating adaptive diversity and evolving through proposition comes from differences in the expression of natural selection [6, 7] and can be regarded as objects atypical and classical scrapie that may make scrapie con- of selection [8, 9]. The extended evolutionary synthesis tagious, historical records of scrapie in Western Europe, [10] is significant in this regard. It caters for evolution in and contemporary accounts of the epidemiology of atyp- the absence of a nucleic acid based genome and allows ical scrapie. Biosecurity preparedness can be based on for evolutionary mechanisms involving prions or pro- current knowledge of pathophysiology and epidemiol- teins that acquire alternative conformations that become ogy and can be built around a three-stage model for the self-propagating [11]. endogenous emergence of a propagating epidemic of The evolvability of prions is substantiated by strain scrapie. The first stage concerns the occurrence of atypi- behaviour in the scrapie agent and has important prac- cal scrapie. The second stage concerns the acquisition of tical consequences for scrapie in sheep [3]. It justifies communicability in prion populations provided by atyp- the proposition that non-contagious idiopathic forms of ical scrapie and the third stage concerns circumstances scrapie, represented arbitrarily by atypical scrapie [12] can allowing disease transmission and the initiation of a be the precursor of classical contagious scrapie. Accord- propagating epidemic. The range of component causes ingly, atypical scrapie is identified as a latent hazard that envisaged for possible outbreaks of endogenous classical can convert to a contagious form under particular circum- scrapie is broad. However, exposure of sheep and goats to stances. The question now is what these circumstances cyanobacterial toxins qualifies for special attention. might be and how they might be managed. The present study reviews relevant knowledge on the natural history of scrapie and the known behaviour of Keywords: Proteostasis; Biosecurity; Neurotoxin; Neuro- prions in the context of evolutionary biology and patho- degenerative physiology. The objective is a preliminary understanding of factors involved in the possible endogenous emergence of classical contagious scrapie from atypical non-conta- gious scrapie and the intent is to inform risk management. Accordingly, (1) differences between atypical and classical scrapie are recapitulated, (2) possible cellular and molec- ular mechanisms underlying the idiopathic genesis of *Corresponding author: David B. Adams, 24 Noala Street, Aranda, atypical scrapie are investigated, (3) the historical record ACT 2614, Australia, Tel: +61 2 6161 4825, E-mail: dadams@home- of scrapie disease in sheep is probed for possible inde- mail.com.au pendent appearances of scrapie at different places and Open Access. © 2019 David B. Adams., published by De Gruyter. This work is licensed under the Creative Commons Attribution 4.0 License. 2 D. B. Adams different times, and (4) accounts of the epidemiological tests based on immunoblotting and immunohistochem- aspects of atypical and Nor98 strain scrapie are analysed. istry. This work used an outstanding collection of case histories to classify the clinical expression of scrapie into five typical syndromes of classical scrapie and five atypi- cal syndromes of scrapie-like illness in sheep. More recent 2 Differences between atypical and studies in 2006 and 2008 [16, 21] list 33 different clini- classical scrapie cal signs of scrapie from four different scientific reports and clustered them under headings of ‘general signs’, A consensus view from the Panel on Biological Hazards ‘changes in behaviour’, ‘changes in sensitivity’, ‘changes of the European Food Safety Authority states that atypical in locomotion’ and ‘other signs’. Symptomatology varied scrapie ‘does not present, epidemiologically, like an infec- according to place and sheep population. Altered mental tious disease’ [12] (EFSA, 2014). A more recent review [13] status, pruritus and wool loss were the most frequent of scrapie disease states similarly that atypical scrapie has initial signs seen in Norway and Spain whereas ataxia a separate aetiology from classical scrapie and is “sponta- and head tremours were the most frequent initial seen in neous or transmits very poorly under natural conditions”. Ireland and both ataxia and pruritis were seen in Italy. Unlike classical scrapie, atypical scrapie is not listed by Characteristics of classical scrapie and atypical scrapie the World Organization for Animal Health (OIE) as a noti- that differ in kind as opposed to degree are the nature and fiable disease [14]. distribution of lesions and deposits of deformed or mis- For present purposes, atypical scrapie is postulated folded prion protein (PrPSc ) in the central nervous system, as non-contagious scrapie and its comparison with con- the tissue distribution of infectivity and misfolded prion tagious classical scrapie can identify features associated protein (PrPSc) and the immunoblot pattern. These first with the capability for contagion. In this regard, future two differences may point to mechanisms that are present instances where atypical scrapie is found to be contagious in classical scrapie and which are required for atypical will not refute the possibility of non-contagious scrapie scrapie to become contagious. The significance of the or the cogency of earlier accounts of atypical scrapie. third difference, the presence of a fourth band of 15 kDa in Instead, they will fortify the present thesis that atypical the immunoblot pattern seen atypical scrapie, is unclear. scrapie has a potential for transforming to contagious As to the first difference, there can be no contagion scrapie when particular circumstances apply. if prions are restricted to the central nervous system and A review of key aspects of classical and atypical thus have no access to the portals of exit known to be scrapie, including Nor98 scrapie [15], shows that some involved in the transmission of contagious scrapie. In characteristics in classical compared with atypical scrapie this regard, PrPSc has been found in the brain of sheep differ in degree whereas other characteristics differ in with atypical scrapie but not in peripheral tissues [22, 23]. kind [3]. Differences in degree may reflect the diversity of By contrast, PrPSc is found in both brain and peripheral variants within population of prions involved in classical tissues in sheep with classical scrapie [24-26]. Particular- and atypical scrapie and point to scope for evolutionary ities in the nature and distribution of lesions and in the change. Differences in kind, however, may foreshadow central nervous system of sheep with atypical or classical gains-of-function in prion populations that can allow the scrapie [27, 28] may identify portals of exit of the scrapie conversion of non-contagious atypical scrapie to conta- agent to peripheral tissues and suggest possible patho- gious scrapie. physiological mechanisms for the migration of scrapie Characters of classical scrapie and atypical scrapie prions to the rest of the body. that differ in degree as opposed to kind are age of onset The second difference in kind between atypical and of disease, symptomatology and duration of disease. classical scrapie is also relevant to the portals of exit that The tendency for atypical scrapie to occur in older sheep make scrapie contagious. The presence of PrPSc and infec- [16-18] may reflect the aetiological importance of host and tivity in the lymphoreticular tissues and cells is a constant environment rather than exposure to exogenous infec- feature in sheep with contagious classical scrapie [24- tion, which drives classical scrapie. Classical and atypical 26]. In contrast, PrPSc is virtually restricted to the central scrapie have exceptionally diverse signs and symptoms nervous system and is scant in the lymphoreticular that vary according to place, time and population and tissues and cells of sheep with atypical scrapie [22, 28]. signal the extent of variation in the scrapie agent. For This difference is crucial because the well-known migra- example, the work of Parry [19, 20], carried out from 1950 tory behaviour of lymphocytes and mononuclear phago-