Accumulation of Pathological Prion Protein PrP ^Sc in the Skin of Animals with Experimental and Natural Scrapie

Abstract

Prion infectivity and its molecular marker, the pathological prion protein PrP ^Sc, accumulate in the central nervous system and often also in lymphoid tissue of animals or humans affected by transmissible spongiform encephalopathies. Recently, PrP ^Sc was found in tissues previously considered not to be invaded by prions (e.g., skeletal muscles). Here, we address the question of whether prions target the skin and show widespread PrP ^Sc deposition in this organ in hamsters perorally or parenterally challenged with scrapie. In hamsters fed with scrapie, PrP ^Sc was detected before the onset of symptoms, but the bulk of skin-associated PrP ^Sc accumulated in the clinical phase. PrP ^Sc was localized in nerve fibres within the skin but not in keratinocytes, and the deposition of PrP ^Sc in skin showed no dependence from the route of infection and lymphotropic dissemination. The data indicated a neurally mediated centrifugal spread of prions to the skin. Furthermore, in a follow-up study, we examined sheep naturally infected with scrapie and detected PrP ^Sc by Western blotting in skin samples from two out of five animals. Our findings point to the skin as a potential reservoir of prions, which should be further investigated in relation to disease transmission.

Author Summary

Transmissible spongiform encephalopathies (TSEs), or prion diseases, are fatal neurodegenerative diseases affecting the central nervous system. According to the prion hypothesis, TSEs are caused by proteinaceous infectious particles (“prions”) that consist essentially of PrP ^Sc, an aberrant form of the prion protein with a pathologically altered folding and/or aggregation structure. Scrapie of sheep, chronic wasting disease (CWD) of deer, bovine spongiform encephalopathy (BSE) of cattle, and variant Creutzfeldt-Jakob disease (vCJD) of humans are prominent examples of acquired prion diseases. To further pinpoint the peripheral tissues that could serve as reservoirs of prions in the mammalian body and from which these pathogens could be potentially disseminated into the environment and transmitted to other individuals, we examined the skin of hamsters perorally challenged with scrapie and of naturally infected scrapie sheep for the presence of PrP ^Sc. We show that PrP ^Sc can accumulate in the skin at late stages of incubation, and that the protein is located primarily in small nerve fibres within this organ. The question of whether the skin may also provide a reservoir for prions in CWD, BSE, or vCJD, and the role of the skin in relation to the natural transmission of scrapie in the field needs further investigation.