Publications by authors named "Wiebke M Wemheuer"

12 Publications

  • Page 1 of 1

Correction to: Unexpected high frequency of neurofibroma in the celiac ganglion of German cattle.

Vet Res 2020 Oct 15;51(1):130. Epub 2020 Oct 15.

Institute of Neuropathology, Medical Faculty of the Saarland University, Homburg, Germany.

An amendment to this paper has been published and can be accessed via the original article.
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http://dx.doi.org/10.1186/s13567-020-00855-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559756PMC
October 2020

Unexpected high frequency of neurofibroma in the celiac ganglion of German cattle.

Vet Res 2020 Jun 17;51(1):82. Epub 2020 Jun 17.

Institute of Neuropathology, Medical Faculty of the Saarland University, Homburg, Germany.

In a study originally designed to find potential risk factors for bovine spongiform encephalopathy (BSE) we examined tissues from 403 Holstein Frisian cattle in total. These included 20 BSE cattle and their 236 birth- and feeding cohort animals plus 32 offspring, 103 age, breed and district-matched control cattle and further twelve cattle with neurological signs. In addition to the obex, we examined the celiac ganglion, cervical cranial ganglion, trigeminal ganglion and proximal ganglion of the vagus nerve using histological techniques. Unexpectedly, we found a high number of neurofibroma, a benign peripheral nerve sheath tumor consisting of Schwann cells, fibroblasts and perineural cells. The neurofibroma were present only in the celiac ganglion and found during histologic examination. With a frequency of 9.91% in BSE cattle and their cohorts (case animals) and 9.09% in the age, breed and district matched control animals there seems to be no correlation between the occurrence of BSE and neurofibroma. Benign peripheral nerve sheath tumors have been described more often in cattle than in other domestic animals. Usually, they are incidental macroscopic findings in the thoracic ganglia during meat inspection. To our knowledge, there are no previous systematic histologic studies including bovine celiac ganglia at all. The high incidence of celiac ganglia neurofibroma may play a role in the frequently occurring abomasal displacements in Holstein Frisian cattle as the tumors might cause a gastrointestinal motility disorder. At present a genetic predisposition for these neoplasms cannot be ruled out.
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http://dx.doi.org/10.1186/s13567-020-00800-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301510PMC
June 2020

Morgagnian cataract resulting from a naturally occurring nonsense mutation elucidates a role of CPAMD8 in mammalian lens development.

PLoS One 2017 6;12(7):e0180665. Epub 2017 Jul 6.

University of Goettingen, Institute of Veterinary Medicine, Goettingen, Germany.

To investigate the genetic basis of hereditary lens opacities we analyzed 31 cases of bilateral congenital cataract in Red Holstein Friesian cattle. A genome-wide association study revealed a significant association on bovine chromosome 7 at positions 6,166,179 and 12,429,691. Whole genome re-sequencing of one case and four relatives showed a nonsense mutation (g.5995966C>T) in the PZP-like, alpha-2-macroglobulin domain containing 8 (CPAMD8) gene leading to a premature stop codon (CPAMD8 p.Gln74*) associated with cataract development in cattle. With immunohistochemistry we confirmed a physiological expression of CPAMD8 in the ciliary body epithelium of the eye in unaffected cattle, while the protein was not detectable in the ciliary body of cattle with cataracts. RNA expression of CPAMD8 was detected in healthy adult, fetal and cataractous lenses.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180665PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500361PMC
October 2017

Types and Strains: Their Essential Role in Understanding Protein Aggregation in Neurodegenerative Diseases.

Front Aging Neurosci 2017 16;9:187. Epub 2017 Jun 16.

Institute of Neuropathology, Saarland University Medical CenterHomburg, Germany.

Protein misfolding and aggregation is a key event in diseases like Alzheimer's disease (AD) or Parkinson's disease (PD) and is associated with neurodegeneration. Factors that initiate protein misfolding and the role of protein aggregation in the pathophysiology of disease pose major challenges to the neuroscientific community. Interestingly, although the accumulation of the same misfolded protein, e.g., α-synuclein is detectable in all idiopathic PD patients, the disease spectrum covers a variety of different clinical presentations and disease courses. In a more recent attempt this clinical variance is being explained in analogy to prion diseases by different protein aggregate conformations. In prion diseases a relationship between protein aggregate conformation properties and the clinical disease course was shown by relating different prion types to a dementia and an ataxic disease course in Creutzfeldt-Jakob patients. This principle is currently transferred to AD, PD and other neurodegenerative diseases with protein aggregation. However, differences in protein aggregate conformation are frequently addressed as disease strains. The term "strain" also derives from prion research and evolved by adopting the virus terminology at a time when transmissible spongiform encephalopathies (TSEs; later called prion diseases) were assumed to be caused by a virus. The problem is that in virus taxonomy the term "type" refers to properties of the disease agent itself and the term "strain" refers to host associated factors that interact with the disease agent and may moderately modify the clinical disease presentation. Strain factors can be discovered only after transmission and passaging of the agent in a host of a different species. The incorrect use of the terminology confuses disease agent and host factors and hampers the understanding of the pathophysiology of protein aggregate-associated neurodegenerative diseases. In this review article the discoveries are reviewed that explain how the terms "type" and "strain" emerged for unconventional disease agents. This may help to avoid confusion in the terminology of protein aggregation diseases and to reflect correctly the impact of protein aggregate conformation as well as host factor contribution on different clinical variations of AD, PD and other neurodegenerative diseases.
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http://dx.doi.org/10.3389/fnagi.2017.00187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472693PMC
June 2017

Filtration of protein aggregates increases the accuracy for diagnosing prion diseases in brain biopsies.

J Neuropathol Exp Neurol 2013 Aug;72(8):758-67

Department of Neuropathology, Prion and Dementia Research Unit, University Medical Center Göttingen, Germany.

In brain biopsies taken from patients with rapidly progressive dementia, the first differential diagnoses to be ruled out are prion diseases. For safe diagnostic processing of tissue and instruments, a rapid, highly sensitive, and specific analysis for prion aggregates is necessary. Here, we examined 16 brain biopsies and brain samples (frontal cortex and cerebellum) from 65 autopsies by Western blot, paraffin-embedded tissue (PET) blot, immunohistochemistry, and the recently described membrane adsorption assay (MAA) for their suitability to detect pathologic prion protein. In our hands, the PET blot method provided the highest sensitivity in prion detection (biopsies, 100%; all autopsy sections, 96.3%), closely followed by the MAA (biopsies, 100%; all autopsy samples, 96%) and Western blot analysis (biopsies, 100%; all autopsy samples, 92%). Conventional immunohistochemistry is the least sensitive method (biopsies, 50%; all autopsy sections, 80%) and also gave 1 false-positive biopsy result. Consequently, our standard diagnostic protocol is to use the MAA as a first step for detecting or excluding a prion disease, followed by the PET blot for the prion deposition pattern, Western blotting for prion typing, and immunohistochemistry for differential diagnoses. With this standard and the availability of unfixed tissue, a diagnosis was possible in all 16 biopsies examined.
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http://dx.doi.org/10.1097/NEN.0b013e31829d2799DOI Listing
August 2013

Subtype-specific synaptic proteome alterations in sporadic Creutzfeldt-Jakob disease.

J Alzheimers Dis 2013 ;37(1):51-61

National Reference Center for TSE, Medical Center Georg-August University, Goettingen, Germany.

Sporadic Creutzfeldt-Jakob disease (sCJD) is characterized by wide clinical and pathological variability, which is mainly influenced by the conformation of the misfolded prion protein (PrPSc) and by methionine and valine polymorphism at codon 129 of the gene encoding PrP. This heterogeneity likely implies differences in the molecular cascades that lead to the development of certain disease phenotypes. Here, we investigated synaptic proteome patterns in two most common sCJD subtypes (MM1 and VV2) using 2D DIGE and mass spectrometry. We found that 23 distinct proteins were differentially expressed in at least one sCJD subtype when compared to age-matched controls. The majority of these proteins displayed significant subtype-specific alterations, with only up-regulated glial fibrillary acidic protein and down-regulated spectrin alpha chain in both sCJD subtypes. Differentially expressed proteins found in this study are mainly involved in synaptic structure and activity, mitochondrial function, or calcium metabolism. Moreover, several of them have been already linked to the pathophysiological processes occurring in Alzheimer's disease.
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http://dx.doi.org/10.3233/JAD-130455DOI Listing
April 2014

Spongiform encephalopathy in siblings with no evidence of protease-resistant prion protein or a mutation in the prion protein gene.

J Neurol 2013 Jul 2;260(7):1871-9. Epub 2013 Apr 2.

National Reference Center for TSE Surveillance, Department of Neurology, University Medical Center Göttingen, Robert-Koch Str. 40, 37075 Göttingen, Germany.

We discuss relevant aspects in two siblings with a neurodegenerative process of unclear aetiology who developed progressive dementia with global aphasia and hyperoral behaviour at the ages of 39 and 46 years and who died 6 and 5 years after disease onset. The cases were reported to the National Reference Center for TSE Surveillance in Göttingen, Germany. Detailed clinical examinations, CSF, blood samples, and copies of the important diagnostic tests (magnetic resonance imaging, electroencephalogram, laboratory tests) were obtained. Further neuropathological and genetic analyses were performed. Cerebral magnetic resonance imaging of both siblings showed prominent changes in signal intensity, especially in the left medial temporal cortex, but also the hippocampal formation. Neuropathological examination revealed spongiform changes, neuronal loss, and astrocytic gliosis, which are typical in Creutzfeldt-Jakob disease. However, no prion protein deposits were detectable by immunohistochemical analysis, Western blot, or PET blot, though abundant tau protein deposits were observed. A mutation in the coding region of the prion protein genes of both siblings was excluded. A detailed search of the literature revealed no other cases with a similar clinical and neuropathological appearance. While the disease aetiology remains unclear, the findings point to a neurodegenerative process and most likely a genetic disease.
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http://dx.doi.org/10.1007/s00415-013-6897-zDOI Listing
July 2013

Sporadic Creutzfeldt-Jakob disease subtype-specific alterations of the brain proteome: impact on Rab3a recycling.

Proteomics 2012 Dec 12;12(23-24):3610-20. Epub 2012 Dec 12.

National Reference Center for TSE Surveillance, Medical Center Georg-August University, Goettingen, Germany.

Sporadic Creutzfeldt-Jakob disease (sCJD) is characterized by wide clinical and pathological variability, which is mainly influenced by the conformation of the misfolded prion protein, and by the methionine and valine polymorphism at codon 129 of the prion protein gene. This heterogeneity likely implies differences in the molecular cascade that leads to the development of certain disease phenotypes. In this study, we investigated the proteome of the frontal cortex of patients with the two most common sCJD subtypes (MM1 and VV2) using 2D-DIGE and MS. Analysis of 2D maps revealed that 46 proteins are differentially expressed in the sCJD. Common differential expression was detected for seven proteins, four showed opposite direction of differential expression, and the remaining ones displayed subtype-specific alteration. The highest number of differentially expressed proteins was associated with signal transduction and neuronal activity. Moreover, functional groups of proteins involved in cell cycle and death, as well as in structure and motility included subtype-specific expressed proteins exclusively. The expression of Rab GDP dissociation inhibitor alpha, which regulates Rab3a-mediated neurotransmitter release, was affected in both sCJD subtypes that were analyzed. Therefore, we also investigated as to whether Rab3a recycling is altered. Indeed, we found an accumulation of the membrane-associated form, thus the active one, which suggests that dysfunction of the Rab3a-mediated exocytosis might be implicated in sCJD pathology.
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http://dx.doi.org/10.1002/pmic.201200201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565451PMC
December 2012

Detergents modify proteinase K resistance of PrP Sc in different transmissible spongiform encephalopathies (TSEs).

Vet Microbiol 2012 May 14;157(1-2):23-31. Epub 2011 Dec 14.

Prion and Dementia Research Unit, Department of Neuropathology, University Medical Center Göttingen, Robert Koch Str. 40, 37075 Göttingen, Germany.

Prion diseases are diagnosed by the detection of their proteinase K-resistant prion protein fragment (PrP(Sc)). Various biochemical protocols use different detergents for the tissue preparation. We found that the resistance of PrP(Sc) against proteinase K may vary strongly with the detergent used. In our study, we investigated the influence of the most commonly used detergents on eight different TSE agents derived from different species and distinct prion disease forms. For a high throughput we used a membrane adsorption assay to detect small amounts of prion aggregates, as well as Western blotting. Tissue lysates were prepared using DOC, SLS, SDS or Triton X-100 in different concentrations and these were digested with various amounts of proteinase K. Detergents are able to enhance or diminish the detectability of PrP(Sc) after proteinase K digestion. Depending on the kind of detergent, its concentration - but also on the host species that developed the TSE and the disease form or prion type - the detectability of PrP(Sc) can be very different. The results obtained here may be helpful during the development or improvement of a PrP(Sc) detection method and they point towards a detergent effect that can be additionally used for decontamination purposes. A plausible explanation for the detergent effects described in this article could be an interaction with the lipids associated with PrP(Sc) that may stabilize the aggregates.
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http://dx.doi.org/10.1016/j.vetmic.2011.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338006PMC
May 2012

Presence and seeding activity of pathological prion protein (PrP(TSE)) in skeletal muscles of white-tailed deer infected with chronic wasting disease.

PLoS One 2011 Apr 1;6(4):e18345. Epub 2011 Apr 1.

P24-Transmissible Spongiform Encephalopathies, Robert Koch-Institut, Berlin, Germany.

Chronic wasting disease (CWD) is a contagious, rapidly spreading transmissible spongiform encephalopathy (TSE), or prion disease, occurring in cervids such as white tailed-deer (WTD), mule deer or elk in North America. Despite efficient horizontal transmission of CWD among cervids natural transmission of the disease to other species has not yet been observed. Here, we report for the first time a direct biochemical demonstration of pathological prion protein PrP(TSE) and of PrP(TSE)-associated seeding activity, the static and dynamic biochemical markers for biological prion infectivity, respectively, in skeletal muscles of CWD-infected cervids, i. e. WTD for which no clinical signs of CWD had been recognized. The presence of PrP(TSE) was detected by Western- and postfixed frozen tissue blotting, while the seeding activity of PrP(TSE) was revealed by protein misfolding cyclic amplification (PMCA). Semi-quantitative Western blotting indicated that the concentration of PrP(TSE) in skeletal muscles of CWD-infected WTD was approximately 2000-10,000-fold lower than in brain tissue. Tissue-blot-analyses revealed that PrP(TSE) was located in muscle-associated nerve fascicles but not, in detectable amounts, in myocytes. The presence and seeding activity of PrP(TSE) in skeletal muscle from CWD-infected cervids suggests prevention of such tissue in the human diet as a precautionary measure for food safety, pending on further clarification of whether CWD may be transmissible to humans.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0018345PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3069970PMC
April 2011

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

Vet Res 2011 Feb 15;42:32. Epub 2011 Feb 15.

Prion and Dementia Research Unit, Department of Neuropathology, University Medical Center, Georg-August University, Robert-Koch Str, 40, 37075 Goettingen, Germany.

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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http://dx.doi.org/10.1186/1297-9716-42-32DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3050706PMC
February 2011

Similarities between forms of sheep scrapie and Creutzfeldt-Jakob disease are encoded by distinct prion types.

Am J Pathol 2009 Dec 22;175(6):2566-73. Epub 2009 Oct 22.

Prion and Dementia Research Unit, Department of Neuropathology, University Medical Center Goettingen, Goettingen, Germany.

Transmissible spongiform encephalopathies such as scrapie in sheep, Creutzfeldt-Jakob disease (CJD) in humans, and bovine sporadic encephalopathy in cattle are characterized by the accumulation of a misfolded protein: the pathological prion protein. Ever since bovine sporadic encephalopathy was discovered as the likely cause of the new variant of CJD in humans, parallels between human and animal transmissible spongiform encephalopathies must be viewed under the aspect of a disease risk for humans. In our study we have compared prion characteristics of different forms of sheep scrapie with those of different phenotypes of sporadic CJD. The disease characteristics of sporadic CJD depend considerably on the prion type 1 or 2. Our results show that there are obvious parallels between sporadic CJD type 1 and the so-called atypical/Nor98 scrapie. These parelleles apply to the deposition form of pathological prion protein in the brain, detected by the paraffin-embedded-tissue blot and the prion aggregate stability with regard to denaturation by the chaotropic salt guanidine hydrochloride. The same applies to sporadic CJD type 2 and classical scrapie. The observed parallels between types of sporadic CJD and types of sheep scrapie demonstrate that distinct groups of prion disease exist in different species. This should be taken into consideration when discussing interspecies transmission.
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http://dx.doi.org/10.2353/ajpath.2009.090623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2789619PMC
December 2009