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

Wemheuer WM, Benestad SL, Wrede A, Wemheuer WE, Brenig B, Bratberg B, Schulz-Schaeffer WJ - Vet. Res. (2011)

Bottom Line: 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.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Prion and Dementia Research Unit, Department of Neuropathology, University Medical Center, Georg-August University, Robert-Koch Str, 40, 37075 Goettingen, Germany. wjschulz@med.uni-goettingen.de.

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.

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Differences in the neuroanatomical distribution of PrPSc deposit in atypical/Nor98 and classical sheep scrapie: In atypical/Nor98 scrapie, white matter structures like the external capsule or rostral commissure contain substantially more PrPSc than the subcortical nuclei or basal ganglia respectively (a and c), whereas this is the reverse in classical scrapie (b and d). The external capsule (a and b) and the rostral commissure (c and d) are marked with arrows (mAb P4, bars = 1 mm). Tissue derived from sheep with the genotypes ARQ/AHQ (a), ARQ/ARQ (b and d) and AHQ/AFRQ (c).
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Figure 7: Differences in the neuroanatomical distribution of PrPSc deposit in atypical/Nor98 and classical sheep scrapie: In atypical/Nor98 scrapie, white matter structures like the external capsule or rostral commissure contain substantially more PrPSc than the subcortical nuclei or basal ganglia respectively (a and c), whereas this is the reverse in classical scrapie (b and d). The external capsule (a and b) and the rostral commissure (c and d) are marked with arrows (mAb P4, bars = 1 mm). Tissue derived from sheep with the genotypes ARQ/AHQ (a), ARQ/ARQ (b and d) and AHQ/AFRQ (c).

Mentions: In contrast to the classical scrapie cases, differentiating distribution/spread stages of PrPSc in the CNS was not feasible with the atypical/Nor98 scrapie cases. In Figure 6, the same brain sections that illustrate the different stages of classical scrapie in Figure 2 are depicted for a case of atypical/Nor98 scrapie. In all atypical/Nor98 scrapie sheep, where brainstem material was available (n = 15) apart from one (see below), PrPSc aggregates were detectable in the rhombencephalon and mesencephalon. Regularly affected neuroanatomical structures were the spinal trigeminal nucleus, reticular formation, pyramid, pontine fibres, substantia nigra and cerebral peduncle. In the spinal cord the corticospinal tract and substantia gelatinosa accumulated PrPSc in most cases (Figure 1c). Certain grey matter structures such as the DMNV, hypoglossal nucleus, dorsal tegmental nucleus, oculomotor nucleus, red nucleus and central grey of the mesencephalon, never displayed any PrPSc in the examined atypical/Nor98 scrapie cases. These listed neuroanatomical sites, however, accumulated large amounts of PrPSc in the respective stage of PrPSc distribution in the CNS of classical scrapie sheep as explained above (Figures 2, 3, 4 and 5). There were no PrPSc aggregates detectable in the cerebellar nuclei of the examined atypical/Nor98 scrapie cases, in contrast to the classical scrapie cases as described above. The synaptic or reticular PrPSc staining pattern in the cerebellar cortex of atypical/Nor98 scrapie sheep was in most cases more intense in the molecular than in the granular layer (Figure 1e). Intra- and extracellular complex PrPSc aggregates in the cerebellar cortex of classical scrapie sheep were predominantly present in the granular layer and surrounding the Purkinje cells; the molecular layer displayed mainly glia-associated PrPSc deposits that took a stellate form (Figure 1d). The cerebellar peduncles and white matter of the cerebellum itself showed PrPSc aggregates for both scrapie types. In the diencephalon of most atypical/Nor98 scrapie sheep, the corpora geniculata, medial thalamic nuclei and reticular nucleus accumulated PrPSc aggregates. In all atypical/Nor98 cases where the anterior striatum could be examined (n = 14), PrPSc deposits were also present in the caudate nucleus and putamen. The white matter of diencephalon and telencephalon showed PrPSc deposits in both types of sheep scrapie. In atypical/Nor98 scrapie, these were mainly confined to the subcortical fibres and certain white matter tracts, e.g. the corpus callosum or the commissura rostralis (Figure 7d, arrow), while the distribution in classical scrapie was more disseminated.


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

Wemheuer WM, Benestad SL, Wrede A, Wemheuer WE, Brenig B, Bratberg B, Schulz-Schaeffer WJ - Vet. Res. (2011)

Differences in the neuroanatomical distribution of PrPSc deposit in atypical/Nor98 and classical sheep scrapie: In atypical/Nor98 scrapie, white matter structures like the external capsule or rostral commissure contain substantially more PrPSc than the subcortical nuclei or basal ganglia respectively (a and c), whereas this is the reverse in classical scrapie (b and d). The external capsule (a and b) and the rostral commissure (c and d) are marked with arrows (mAb P4, bars = 1 mm). Tissue derived from sheep with the genotypes ARQ/AHQ (a), ARQ/ARQ (b and d) and AHQ/AFRQ (c).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3050706&req=5

Figure 7: Differences in the neuroanatomical distribution of PrPSc deposit in atypical/Nor98 and classical sheep scrapie: In atypical/Nor98 scrapie, white matter structures like the external capsule or rostral commissure contain substantially more PrPSc than the subcortical nuclei or basal ganglia respectively (a and c), whereas this is the reverse in classical scrapie (b and d). The external capsule (a and b) and the rostral commissure (c and d) are marked with arrows (mAb P4, bars = 1 mm). Tissue derived from sheep with the genotypes ARQ/AHQ (a), ARQ/ARQ (b and d) and AHQ/AFRQ (c).
Mentions: In contrast to the classical scrapie cases, differentiating distribution/spread stages of PrPSc in the CNS was not feasible with the atypical/Nor98 scrapie cases. In Figure 6, the same brain sections that illustrate the different stages of classical scrapie in Figure 2 are depicted for a case of atypical/Nor98 scrapie. In all atypical/Nor98 scrapie sheep, where brainstem material was available (n = 15) apart from one (see below), PrPSc aggregates were detectable in the rhombencephalon and mesencephalon. Regularly affected neuroanatomical structures were the spinal trigeminal nucleus, reticular formation, pyramid, pontine fibres, substantia nigra and cerebral peduncle. In the spinal cord the corticospinal tract and substantia gelatinosa accumulated PrPSc in most cases (Figure 1c). Certain grey matter structures such as the DMNV, hypoglossal nucleus, dorsal tegmental nucleus, oculomotor nucleus, red nucleus and central grey of the mesencephalon, never displayed any PrPSc in the examined atypical/Nor98 scrapie cases. These listed neuroanatomical sites, however, accumulated large amounts of PrPSc in the respective stage of PrPSc distribution in the CNS of classical scrapie sheep as explained above (Figures 2, 3, 4 and 5). There were no PrPSc aggregates detectable in the cerebellar nuclei of the examined atypical/Nor98 scrapie cases, in contrast to the classical scrapie cases as described above. The synaptic or reticular PrPSc staining pattern in the cerebellar cortex of atypical/Nor98 scrapie sheep was in most cases more intense in the molecular than in the granular layer (Figure 1e). Intra- and extracellular complex PrPSc aggregates in the cerebellar cortex of classical scrapie sheep were predominantly present in the granular layer and surrounding the Purkinje cells; the molecular layer displayed mainly glia-associated PrPSc deposits that took a stellate form (Figure 1d). The cerebellar peduncles and white matter of the cerebellum itself showed PrPSc aggregates for both scrapie types. In the diencephalon of most atypical/Nor98 scrapie sheep, the corpora geniculata, medial thalamic nuclei and reticular nucleus accumulated PrPSc aggregates. In all atypical/Nor98 cases where the anterior striatum could be examined (n = 14), PrPSc deposits were also present in the caudate nucleus and putamen. The white matter of diencephalon and telencephalon showed PrPSc deposits in both types of sheep scrapie. In atypical/Nor98 scrapie, these were mainly confined to the subcortical fibres and certain white matter tracts, e.g. the corpus callosum or the commissura rostralis (Figure 7d, arrow), while the distribution in classical scrapie was more disseminated.

Bottom Line: 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.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Prion and Dementia Research Unit, Department of Neuropathology, University Medical Center, Georg-August University, Robert-Koch Str, 40, 37075 Goettingen, Germany. wjschulz@med.uni-goettingen.de.

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.

Show MeSH
Related in: MedlinePlus