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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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Accumulation of PrPSc in different brain regions during disease progression: The four stages of the examined classical scrapie cases are depicted in four overlying graphs that illustrate how PrPSc aggregates (PET blot method, mAb P4) are increasingly accumulated in the brains from caudal (left) to rostral (right). Evaluation of PrPSc intensity was performed on a scale from 0.5 - 4 (see material and methods) and shown for the following brain areas: 1 dorsal motor nucleus of the vagus nerve (DMNV), 2 inferior olive, 3 dorsal tegmental nucleus, 4 cerebellar molecular layer, 5 cerebellar granular layer, 6 cerebral peduncle, 7 central grey (mesencephalon), 8 caudate nucleus, 9 ventral pallidum, 10 rostral commissure, 11 cruciate sulcus, 12 frontal white matter.
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Figure 4: Accumulation of PrPSc in different brain regions during disease progression: The four stages of the examined classical scrapie cases are depicted in four overlying graphs that illustrate how PrPSc aggregates (PET blot method, mAb P4) are increasingly accumulated in the brains from caudal (left) to rostral (right). Evaluation of PrPSc intensity was performed on a scale from 0.5 - 4 (see material and methods) and shown for the following brain areas: 1 dorsal motor nucleus of the vagus nerve (DMNV), 2 inferior olive, 3 dorsal tegmental nucleus, 4 cerebellar molecular layer, 5 cerebellar granular layer, 6 cerebral peduncle, 7 central grey (mesencephalon), 8 caudate nucleus, 9 ventral pallidum, 10 rostral commissure, 11 cruciate sulcus, 12 frontal white matter.

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)

Accumulation of PrPSc in different brain regions during disease progression: The four stages of the examined classical scrapie cases are depicted in four overlying graphs that illustrate how PrPSc aggregates (PET blot method, mAb P4) are increasingly accumulated in the brains from caudal (left) to rostral (right). Evaluation of PrPSc intensity was performed on a scale from 0.5 - 4 (see material and methods) and shown for the following brain areas: 1 dorsal motor nucleus of the vagus nerve (DMNV), 2 inferior olive, 3 dorsal tegmental nucleus, 4 cerebellar molecular layer, 5 cerebellar granular layer, 6 cerebral peduncle, 7 central grey (mesencephalon), 8 caudate nucleus, 9 ventral pallidum, 10 rostral commissure, 11 cruciate sulcus, 12 frontal white matter.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Accumulation of PrPSc in different brain regions during disease progression: The four stages of the examined classical scrapie cases are depicted in four overlying graphs that illustrate how PrPSc aggregates (PET blot method, mAb P4) are increasingly accumulated in the brains from caudal (left) to rostral (right). Evaluation of PrPSc intensity was performed on a scale from 0.5 - 4 (see material and methods) and shown for the following brain areas: 1 dorsal motor nucleus of the vagus nerve (DMNV), 2 inferior olive, 3 dorsal tegmental nucleus, 4 cerebellar molecular layer, 5 cerebellar granular layer, 6 cerebral peduncle, 7 central grey (mesencephalon), 8 caudate nucleus, 9 ventral pallidum, 10 rostral commissure, 11 cruciate sulcus, 12 frontal white matter.
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