Coincident Scrapie Infection and Nephritis Lead to Urinary Prion Excretion

Seeger, Harald; Heikenwälder, Mathias; Zeller, Nicolas; Kranich, Jan; Schwarz, Petra; Gaspert, Ariana; Seifert, Burkhardt; Miele, Gino; Aguzzi, Adriano

doi:10.1126/science.1118829

Cited by 168 publications

(126 citation statements)

References 16 publications

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“…However, there are studies that are not consistent with these findings (26,27). Perhaps unrecognized nephritic conditions may underlie these discrepant observations, because it has been reported that urinary prion excretion is found only in scrapie-infected mice with lymphocytic nephritis (28). In this study, we observed several bands with high molecular weights that reacted with anti-cheetah AA antiserum in the whole urine sample, but not in the urine pellet in which AA amyloid fibrils should be recovered.…”

Section: Discussionmentioning

confidence: 55%

Fecal transmission of AA amyloidosis in the cheetah contributes to high incidence of disease

Zhang

Une

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

111

107

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AA amyloidosis is one of the principal causes of morbidity and mortality in captive cheetahs (Acinonyx jubatus), which are in danger of extinction, but little is known about the underlying mechanisms. Given the transmissible characteristics of AA amyloidosis, transmission between captive cheetahs may be a possible mechanism involved in the high incidence of AA amyloidosis. In this study of animals with AA amyloidosis, we found that cheetah feces contained AA amyloid fibrils that were different from those of the liver with regard to molecular weight and shape and had greater transmissibility. The infectious activity of fecal AA amyloid fibrils was reduced or abolished by the protein denaturants 6 M guanidine⅐HCl and formic acid or by AA immunodepletion. Thus, we propose that feces are a vehicle of transmission that may accelerate AA amyloidosis in captive cheetah populations. These results provide a pathogenesis for AA amyloidosis and suggest possible measures for rescuing cheetahs from extinction.feces ͉ transmissibility

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Section: Discussionmentioning

confidence: 55%

Fecal transmission of AA amyloidosis in the cheetah contributes to high incidence of disease

Zhang

Une

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

111

107

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“…Quantification was performed on a Storm PhosphorImager System (Amersham Biosciences). Antibodies used were as follows: 3F4 monoclonal anti-PrP antibody (Signet Laboratories) at 1:2500; POM1 anti-PrP antibody (25,26) Immunohistochemical Staining-The tissue processing for immunohistochemical staining was performed as described previously (19). The anti-cPLA 2 antibody (Santa Cruz Biotechnology) was used at 1:50.…”

Section: Methodsmentioning

confidence: 99%

The Interaction between Cytoplasmic Prion Protein and the Hydrophobic Lipid Core of Membrane Correlates with Neurotoxicity

Wang

Arterburn

et al. 2006

Journal of Biological Chemistry

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Prion protein (PrP), normally a cell surface protein, has been detected in the cytosol of a subset of neurons. The appearance of PrP in the cytosol could result from either retro-translocation of misfolded PrP from the endoplasmic reticulum (ER) or impaired import of PrP into the ER. Transgenic mice expressing cytoplasmic PrP (cyPrP) developed neurodegeneration in cerebellar granular neurons, although no detectable pathology was observed in other brain regions. In order to understand why granular neurons in the cerebellum were most susceptible to cyPrP-induced degeneration, we investigated the subcellular localization of cyPrP. Interestingly, we found that cyPrP is membrane-bound. In transfected cells, it binds to the ER and plasma/endocytic vesicular membranes. In transgenic mice, it is associated with synaptic and microsomal membranes. Furthermore, the cerebellar neurodegeneration in transgenic mice correlates with the interaction between cyPrP and the hydrophobic lipid core of the membrane but not with either the aggregation status or the dosage of cyPrP. These results suggest that lipid membrane perturbation could be a cellular mechanism for cyPrP-induced neurotoxicity and explain the seemingly conflicting results concerning cyPrP.Prion diseases are a group of fatal neurodegenerative disorders that are sporadic, inherited, or transmissible (1). The resistance of PrP 2 knock-out mice to prion disease revealed the essential role of endogenous PrP in developing the two characteristics of prion disease, infectivity and neurodegeneration (2). In prion disease, a portion of PrP converts from its normal conformation, PrP C , to an insoluble and protease-resistant pathogenic conformation, PrP Sc (1). Compelling evidence supports that PrP Sc is the transmissible element in prion disease (3-5).Newly synthesized PrP contains an N-terminal signal sequence, which directs PrP to be co-translationally imported into the lumen of the ER. The signal sequence is cleaved within the ER, along with a C-terminal glycosylphosphatidylinositol signal sequence that is responsible for glycosylphosphatidylinositol anchor addition (6). Once folded correctly, PrP passes through the ER quality control machinery, maturing along the secretory pathway en route to the cell surface. In addition to cell surface and luminal localizations, cytosolic localized PrP has also been detected (7,8). Recent studies revealed that the cytosolic appearance of PrP could result from two independent but not mutually exclusive pathways. In a variety of cell lines, including primary neurons expressing endogenous PrP, it has been found that some PrP molecules misfold in the ER and are retro-translocated to the cytosol for proteasome degradation via the ER-associated degradation pathway (9 -13). Disease-associated PrP mutants have an increased tendency to misfold and are subjected to ER-associated degradation (9,10,12). An alternative pathway, the unsuccessful import of PrP because of the insufficiency of the PrP signal sequence, was revealed by an elegant study in...

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“…Perhaps multiple exposure pathways can lead to an infection, nevertheless, horizontal spread of CWD is clearly Inflammation may increase the risk of prion shedding in cervids. In prion-infected mice, follicular inflammation in the kidney directs prions to accumulate within lymphoid follicles [21] and intriguingly, leads to prion excretion into the urine of infected mice [22]. Even in natural sheep scrapie cases, follicular mastitis results in prion accumulation in the mammary gland [23].…”

Section: Transmission Among Cervidsmentioning

confidence: 99%

28.7 Chronic wasting disease

Selbitz¹,

Truyen²,

Valentin‐Weigand³

2015

Tiermedizinische Mikrobiologie, Infektions- Und Seuchenlehre

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Until recently, chronic wasting disease of cervids, the only wildlife prion disease, was believed to be geographically concentrated to Colorado and Wyoming within the United States. However, increased surveillance has unveiled several additional pockets of CWD-infected deer and elk in 12 additional states and 2 Canadian provinces. Deer and elk with CWD have extensive aggregates of PrP Sc not only in the central nervous system, but also in peripheral lymphoid tissues, skeletal muscle, and other organs, perhaps influencing prion shedding. Indeed, CWD is transmitted efficiently among animals by horizontal routes, although the mechanism of spread is unknown. Genetic polymorphisms in the Prnp gene may affect CWD susceptibility, particularly at codon 225 (S/F) in deer and codon 132 (M/L) in elk. Since CWD infects free-ranging animals and is efficiently spread, disease management will be a challenge. A chronicle of CWDA prion disease of free-ranging wildlife, chronic wasting disease (CWD) affects mule deer (Odocoileus hemionus), white-tailed deer (O. virginianus), Rocky Mountain elk (Cervus elaphus nelsoni) [1], and moose (Alces alces shirasi) [2], all members of the family Cervidae. CWD was first noted in 1967 within a research facility in Fort Collins, Colorado where captive mule deer used for nutrition research were reported with a body wasting syndrome [2]. After more than a decade of uncertainty about the etiology of CWD, pathologists Elizabeth Williams and Stewart Young recognized the brain lesions as those of a transmissible spongiform encephalopathy (TSE) in 1978, and CWD was subsequently demonstrated as a prion disease not only by the classic neuronal perikaryonic vacuoles [3], but also by the accumulation of aggregated prion protein [4] (Fig. 1) as well as prion infectivity in the brain [5]. In the late 70s and early 80s, CWD was detected in two zoological collections, in Wyoming and in Canada [6]. Beginning in 1981, cases of CWD were discovered in wild deer and elk on the eastern slope of the Rocky Mountains and extending out on the plains following river valleys within Colorado and Wyoming [7,8]. By 1996, CWD was first detected in Canada's farmed elk, and soon thereafter in the US elk industry, although it may have occurred in this industry far earlier.More recently, CWD-infected ranched elk have been discovered in several other US states and in South Korea [9] [10] raising international awareness and concern regarding CWD. The origin of CWD remains an enigma.*Corresponding author e-mail: E-mail: csigurd@lamar.colostate.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the jou...

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Coincident Scrapie Infection and Nephritis Lead to Urinary Prion Excretion

Cited by 168 publications

References 16 publications

Fecal transmission of AA amyloidosis in the cheetah contributes to high incidence of disease

Fecal transmission of AA amyloidosis in the cheetah contributes to high incidence of disease

The Interaction between Cytoplasmic Prion Protein and the Hydrophobic Lipid Core of Membrane Correlates with Neurotoxicity

28.7 Chronic wasting disease

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