PrPSc spreading patterns in the brain of sheep linked to different prion types

Abstract

Scrapie in sheep and goats has been known for more than 250 years and belongs nowadays to the so-called prion diseases that also include e.g. bovine spongiform encephalopathy in cattle (BSE) and Creutzfeldt-Jakob disease in humans. According to the prion hypothesis, the pathological isoform (PrPSc) of the cellular prion protein (PrPc) comprises the essential, if not exclusive, component of the transmissible agent. Currently, two types of scrapie disease are known - classical and atypical/Nor98 scrapie. In the present study we examine 24 cases of classical and 25 cases of atypical/Nor98 scrapie with the sensitive PET blot method and validate the results with conventional immunohistochemistry. The sequential detection of PrPSc aggregates in the CNS of classical scrapie sheep implies that after neuroinvasion a spread from spinal cord and obex to the cerebellum, diencephalon and frontal cortex via the rostral brainstem takes place. We categorize the spread of PrPSc into four stages: the CNS entry stage, the brainstem stage, the cruciate sulcus stage and finally the basal ganglia stage. Such a sequential development of PrPSc was not detectable upon analysis of the present atypical/Nor98 scrapie cases. PrPSc distribution in one case of atypical/Nor98 scrapie in a presumably early disease phase suggests that the spread of PrPSc aggregates starts in the di- or telencephalon. In addition to the spontaneous generation of PrPSc, an uptake of the infectious agent into the brain, that bypasses the brainstem and starts its accumulation in the thalamus, needs to be taken into consideration for atypical/Nor98 scrapie.

Atypical Scrapie Isolates Involve a Uniform Prion Species with a Complex Molecular Signature

“…Similar findings were later reported by other groups in both naturally-occurring cases and following experimental oral transmission of atypical scrapie isolates to sheep [16], [18]–[20]. However, it remains to be determined whether this diversity in PrP d distribution is attributable to host factors, the involvement of particular prion types or a combination of both.…”

Atypical scrapie in Australia

“…The lesion profile of classical scrapie (the neuroanatomical distribution of vacuolation and PrP Sc immunolabelling of neuronal cytoplasm and grey matter neuropil within the CNS) reflects the pathogenesis of neuro‐invasion following oral infection. The scrapie agent spreads from the gut via the vagus nerve to the DMNV in the caudal brainstem and via the splanchnic nerve to the intermediolateral column (lateral horn) in the thoracic spinal cord; from these CNS sites, infection and associated lesions spread in ascending and descending directions throughout the neuraxis . At clinical endpoint, PrP Sc immunolabelling occurs throughout the neuraxis at a moderate to marked severity …”

Disease characteristics of bovine spongiform encephalopathy following inoculation into mice via three different routes

“…; Wemheuer et al . ). However, the mean incubation period following oral challenge correlates with previously published results using IM mice (González et al .…”

“…; Mabbott & MacPherson ; Wemheuer et al . ). If the target areas responsible for clinical signs are affected more by the agent, this potentially has an effect on the level of vacuolation and PrP Sc intensity in the brain of the mouse (Ayers et al .…”