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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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Classification of the PrPSc spread during disease development in classical scrapie.The examined classical scrapie cases classified into four stages of PrP spread  according to certain affected neuroanatomical sites (PET blots, mAb P4). In the CNS entry stage (a - d) only discrete PrPSc deposits are visible in the obex region, while in the brainstem stage (e - h) PrPSc aggregates are clearly visible in the brainstem and start to appear in more rostral structures. Once PrPSc deposits can be found in the deep cortical layers of the frontal cortex (i), the cruciate sulcus stage (i - l) is reached. In the basal ganglia stage, intense deposits in basal ganglia and thalamic nuclei can be found (m - p). Brain sections shown for the first, third and fourth stage derived from sheep with the genotype ARQ/ARQ while the sheep whose brain sections are depicted in the brainstem stage carried the genotype ARH/VRQ (bar = 5 mm).
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Figure 2: Classification of the PrPSc spread during disease development in classical scrapie.The examined classical scrapie cases classified into four stages of PrP spread according to certain affected neuroanatomical sites (PET blots, mAb P4). In the CNS entry stage (a - d) only discrete PrPSc deposits are visible in the obex region, while in the brainstem stage (e - h) PrPSc aggregates are clearly visible in the brainstem and start to appear in more rostral structures. Once PrPSc deposits can be found in the deep cortical layers of the frontal cortex (i), the cruciate sulcus stage (i - l) is reached. In the basal ganglia stage, intense deposits in basal ganglia and thalamic nuclei can be found (m - p). Brain sections shown for the first, third and fourth stage derived from sheep with the genotype ARQ/ARQ while the sheep whose brain sections are depicted in the brainstem stage carried the genotype ARH/VRQ (bar = 5 mm).

Mentions: To determine the sequential appearance of PrPSc in the CNS, all field cases of classical scrapie were subjected to a thorough examination regarding the anatomical structures affected by PrPSc deposition. In the following, all cases were arranged according to the amount of PrPSc they had accumulated in total, and the occurrence of PrPSc in a panel of 127 neuroanatomical loci was compared between the cases. From this evaluation arose a classification of the classical scrapie cases into four stages of PrPSc spread in the CNS (see Figures 2, 3, 4 and 5). Criteria for these turned out to be certain neuroanatomical structures whose involvement marked a stage, meaning that the respective structure accumulated PrPSc aggregates (with a minimal score of 1) in all animals belonging to this stage and the following stage/stages. They are described in detail below and visualized in Figures 3 and 4.


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)

Classification of the PrPSc spread during disease development in classical scrapie.The examined classical scrapie cases classified into four stages of PrP spread  according to certain affected neuroanatomical sites (PET blots, mAb P4). In the CNS entry stage (a - d) only discrete PrPSc deposits are visible in the obex region, while in the brainstem stage (e - h) PrPSc aggregates are clearly visible in the brainstem and start to appear in more rostral structures. Once PrPSc deposits can be found in the deep cortical layers of the frontal cortex (i), the cruciate sulcus stage (i - l) is reached. In the basal ganglia stage, intense deposits in basal ganglia and thalamic nuclei can be found (m - p). Brain sections shown for the first, third and fourth stage derived from sheep with the genotype ARQ/ARQ while the sheep whose brain sections are depicted in the brainstem stage carried the genotype ARH/VRQ (bar = 5 mm).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Classification of the PrPSc spread during disease development in classical scrapie.The examined classical scrapie cases classified into four stages of PrP spread according to certain affected neuroanatomical sites (PET blots, mAb P4). In the CNS entry stage (a - d) only discrete PrPSc deposits are visible in the obex region, while in the brainstem stage (e - h) PrPSc aggregates are clearly visible in the brainstem and start to appear in more rostral structures. Once PrPSc deposits can be found in the deep cortical layers of the frontal cortex (i), the cruciate sulcus stage (i - l) is reached. In the basal ganglia stage, intense deposits in basal ganglia and thalamic nuclei can be found (m - p). Brain sections shown for the first, third and fourth stage derived from sheep with the genotype ARQ/ARQ while the sheep whose brain sections are depicted in the brainstem stage carried the genotype ARH/VRQ (bar = 5 mm).
Mentions: To determine the sequential appearance of PrPSc in the CNS, all field cases of classical scrapie were subjected to a thorough examination regarding the anatomical structures affected by PrPSc deposition. In the following, all cases were arranged according to the amount of PrPSc they had accumulated in total, and the occurrence of PrPSc in a panel of 127 neuroanatomical loci was compared between the cases. From this evaluation arose a classification of the classical scrapie cases into four stages of PrPSc spread in the CNS (see Figures 2, 3, 4 and 5). Criteria for these turned out to be certain neuroanatomical structures whose involvement marked a stage, meaning that the respective structure accumulated PrPSc aggregates (with a minimal score of 1) in all animals belonging to this stage and the following stage/stages. They are described in detail below and visualized in Figures 3 and 4.

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