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From: TSS ()
Subject: Accumulation of Pathological Prion Protein PrPSc in the Skin of Animals with Experimental and Natural Scrapie
Date: May 30, 2007 at 12:54 pm PST

Accumulation of Pathological Prion Protein PrPSc in the Skin of Animals with Experimental and Natural Scrapie

Achim Thomzig1[*, Walter Schulz-Schaeffer2[, Arne Wrede2, Wilhelm Wemheuer3, Bertram Brenig3, Christine Kratzel1,
Karin Lemmer1, Michael Beekes1*

1 P24 Transmissible Spongiform Encephalopathies, Robert Koch-Institut, Berlin, Germany, 2 Prion and Dementia Research Unit, Department of Neuropathology,
Universita¨tsklinikum Go¨ ttingen, Go¨ ttingen, Germany, 3 Institute of Veterinary Medicine, Georg-August-Universita¨t Go¨ ttingen, Go¨ ttingen, Germany

Prion infectivity and its molecular marker, the pathological prion protein PrPSc, accumulate in the central nervous
system and often also in lymphoid tissue of animals or humans affected by transmissible spongiform
encephalopathies. Recently, PrPSc 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 PrPSc
deposition in this organ in hamsters perorally or parenterally challenged with scrapie. In hamsters fed with scrapie,
PrPSc was detected before the onset of symptoms, but the bulk of skin-associated PrPSc accumulated in the clinical
phase. PrPSc was localized in nerve fibres within the skin but not in keratinocytes, and the deposition of PrPSc 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 PrPSc 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
Citation: Thomzig A, Schulz-Schaeffer W, Wrede A, Wemheuer W, Brenig B, et al. (2007) Accumulation of pathological prion protein PrPSc in the skin of animals with
experimental and natural scrapie. PLoS Pathog 3(5): e66. doi:10.1371/journal.ppat.0030066


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 PrPSc, 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 PrPSc. We show
that PrPSc 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.


BSE-Associated PrPSc in the Skin

To test whether not only scrapie-associated PrPSc but also
BSE-associated PrPSc accumulates in the skin, hamsters were
intracerebrally infected with a hamster-adapted BSE (BSE-H)
agent and sacrificed at the end stage of disease. All analyzed
skin specimens from forelimbs and hindlimbs of five donor
animals showed substantial amounts of BSE-associated
PrP27–30 (Figure 4, lanes 1 and 2). Thus, following i.c.
infection, the targeting of BSE-H agent to the skin, as probed
by Western blotting, did not show discernible differences
compared to that observed for 263K scrapie.

PrPSc in Skin Tissue of Sheep Naturally Infected with

In a follow-up proof-of-concept study, which aimed to
validate and expand our findings from the hamster experiments,
five sheep naturally infected with scrapie in the field
were analyzed for the presence of PrPSc in skin specimens
from different body regions (head, snout, hindlimb, forelimb,
perianal, axillar, and inguinal). PrPSc was visualized by
Western blotting after extraction in the form of PrP27–30
from tissue samples using the anti-ovine PrP monoclonal
antibodies ICSM-18 or P4. Positive specimens were found in
two out of the five tested sheep: In sheep Sc3, PrP27–30 was
present in a sample from the inguinal region (Figure 5, lane
5). Sheep Sc5 showed PrP27–30 in a sample from the perianal
region, which was a scratching site of this animal (Figure 5,
lane 6). For control purposes, a deglycosylation of a PrP27–30
extract from the same skin region of this animal was
performed (Figure 5, lane 7). Furthermore, a skin sample
from the snout was found positive for PrP27–30 in animal Sc5
upon detection with the ICSM-18 antibody (Figure 5, lane 8)
and the anti-PrP antibody P4 (Figure 5, lane 9). All other
analyzed skin specimens of the five sheep did not show
specific Western blot signals for PrP27–30. Specimens from
the same skin regions of four uninfected sheep served as
controls and consistently produced negative results (Figure 5,
lanes 10–12).


In this study we have shown that the skin provides a
reservoir for PrPSc, the biochemical marker of prion
infectivity, in five different hamster TSE models, independently
of whether the animals were challenged with scrapie via
the p.o., i.c., or f.p. route, cerebral implantation of scrapiecontaminated
s.w., or i.c. inoculation of a hamster-adapted
BSE agent. Furthermore, PrPSc could be demonstrated for the
first time in skin specimens from sheep naturally infected
with scrapie, though in a limited number of sites investigated
and at low amounts. In a time-course study using hamsters fed
with scrapie agent, we were able to detect PrPSc in the skin
before the onset of clinical symptoms, but the bulk of skinassociated
PrPSc accumulated in the clinical phase of the
disease. From our Western blot findings, the final concentration
of PrPSc in the skin of hamsters seems to be
approximately 5,000–10,000 times lower than that found in
the brain. This would correspond to an infectivity titre of ; 1
3105 to 2 3105 50% i.c. infective doses (ID50i.c.) per gram of
skin tissue. A similar infectivity titre was previously estimated
from Western blot findings for skeletal muscle tissue of
clinically ill hamsters perorally challenged with 263K scrapie

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