Changes in Retinal Function and Morphology Are Early Clinical Signs of Disease in Cattle with Bovine Spongiform Encephalopathy

Greenlee, M. Heather West; Smith, Jodi D.; Platt, Ekundayo M.; Juarez, Jessica R.; Timms, Leo L.; Greenlee, Justin J.

doi:10.1371/journal.pone.0119431

Cited by 19 publications

(46 citation statements)

References 54 publications

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“…The incubation period or clinical duration of the disease in cattle challenged with H-BSE can vary among experiments. 1,17,22 Although the exact reasons for shorter incubation periods or clinical durations remain unknown, this may be due to differences in inoculum titers of the agents (Suppl. Fig.…”

Section: Discussionmentioning

confidence: 99%

Experimental Infection of Cattle With a Novel Prion Derived From Atypical H-Type Bovine Spongiform Encephalopathy

et al. 2017

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H-type bovine spongiform encephalopathy (H-BSE) is an atypical form of BSE in cattle. During passaging of H-BSE in transgenic bovinized (TgBoPrP) mice, a novel phenotype of BSE, termed BSE-SW emerged and was characterized by a short incubation time and host weight loss. To investigate the biological and biochemical properties of the BSE-SW prion, a transmission study was conducted in cattle, which were inoculated intracerebrally with brain homogenate from BSE-SW-infected TgBoPrP mice. The disease incubation period was approximately 15 months. The animals showed characteristic neurological signs of dullness, and severe spongiform changes and a widespread, uniform distribution of disease-associated prion protein (PrP) were observed throughout the brain of infected cattle. Immunohistochemical PrP staining of the brain revealed the presence of intraglial accumulations and plaque-like deposits. No remarkable differences were identified in vacuolar lesion scores, topographical distribution patterns, and staining types of PrP in the brains of BSE-SW- vs H-BSE-infected cattle. PrP deposition was detected in the ganglia, vagus nerve, spinal nerve, cauda equina, adrenal medulla, and ocular muscle. Western blot analysis revealed that the specific biochemical properties of the BSE-SW prion, with an additional 10- to 12-kDa fragment, were well maintained after transmission. These findings indicated that the BSE-SW prion has biochemical properties distinct from those of H-BSE in cattle, although clinical and pathologic features of BSW-SW in cattle are indistinguishable from those of H-BSE. The results suggest that the 2 infectious agents, BSE-SW and H-BSE, are closely related strains.

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Section: Discussionmentioning

confidence: 99%

Experimental Infection of Cattle With a Novel Prion Derived From Atypical H-Type Bovine Spongiform Encephalopathy

et al. 2017

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“…Neuro-inflammation associated with PrP Sc accumulation 4 is likely to exacerbate the functional iron deficiency by sequestering iron within cells, a well-known response to chronic inflammation 14 . Since accumulation of PrP Sc involves conversion of PrP C to a dysfunctional, aggregated form that induces microglial activation 4 , 15 , 16 , it is likely that loss of function of PrP C in iron uptake, aggregation of ferritin, and PrP Sc -induced inflammation evolve simultaneously, making it difficult to identify the contribution of each to iron dyshomeostasis. To differentiate between these processes, it is important to understand the functional role of PrP C in iron uptake, and the effect of PrP Sc and inflammation on iron metabolism at the cellular and organ level in vivo in a relatively simple model where temporal and spatial correlation between the appearance of PrP Sc , microglial activation, and accumulation of ferritin can be mapped during disease progression.…”

Section: Introductionmentioning

confidence: 99%

“…The inner blood-retinal barrier is formed by a monolayer of endothelial cells lining the capillaries that mediate the transport of nutrients from capillary blood to the neuroretina as in the BBB 17 . Furthermore, the neuroretina accumulates PrP Sc and undergoes degeneration in sCJD and scrapie-infected animal models 3 , 16 , 18 – 20 , providing an experimentally manipulable model to understand the role of PrP C in iron transport and the role of PrP Sc and inflammation in retinal iron homeostasis and neuroretinal degeneration.…”

Section: Introductionmentioning

confidence: 99%

Prion protein facilitates retinal iron uptake and is cleaved at the β-site: Implications for retinal iron homeostasis in prion disorders

Asthana

Baksi

Ashok

et al. 2017

Sci Rep

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Prion disease-associated retinal degeneration is attributed to PrP-scrapie (PrPSc), a misfolded isoform of prion protein (PrPC) that accumulates in the neuroretina. However, a lack of temporal and spatial correlation between PrPSc and cytotoxicity suggests the contribution of host factors. We report retinal iron dyshomeostasis as one such factor. PrPC is expressed on the basolateral membrane of retinal-pigment-epithelial (RPE) cells, where it mediates uptake of iron by the neuroretina. Accordingly, the neuroretina of PrP-knock-out mice is iron-deficient. In RPE19 cells, silencing of PrPC decreases ferritin while over-expression upregulates ferritin and divalent-metal-transporter-1 (DMT-1), indicating PrPC-mediated iron uptake through DMT-1. Polarization of RPE19 cells results in upregulation of ferritin by ~10-fold and β-cleavage of PrPC, the latter likely to block further uptake of iron due to cleavage of the ferrireductase domain. A similar β-cleavage of PrPC is observed in mouse retinal lysates. Scrapie infection causes PrPSc accumulation and microglial activation, and surprisingly, upregulation of transferrin despite increased levels of ferritin. Notably, detergent-insoluble ferritin accumulates in RPE cells and correlates temporally with microglial activation, not PrPSc accumulation, suggesting that impaired uptake of iron by PrPSc combined with inflammation results in retinal iron-dyshomeostasis, a potentially toxic host response contributing to prion disease-associated pathology.

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“…The retina is part of the CNS and is affected by numerous protein misfolding diseases, including Alzheimer disease, 9 Parkinson disease, 10e12 and numerous TSEs, including scrapie in sheep, 13,14 chronic wasting disease in cervids, 15e17 bovine spongiform encephalopathy in cattle, 18,19 and Creutzfeldt-Jakob disease in humans. 20,21 The retina and associated visual structures provide an excellent model to study the transport of misfolded proteins from one CNS structure to another.…”

mentioning

confidence: 99%

Temporal Resolution of Misfolded Prion Protein Transport, Accumulation, Glial Activation, and Neuronal Death in the Retinas of Mice Inoculated with Scrapie

Greenlee

Lind

Kokemuller

et al. 2016

The American Journal of Pathology

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Currently, there is a lack of pathological landmarks to describe the progression of prion disease in vivo. Our goal was to use an experimental model to determine the temporal relationship between the transport of misfolded prion protein (PrP Sc ) from the brain to the retina, the accumulation of PrP Sc in the retina, the response of the surrounding retinal tissue, and loss of neurons. Retinal samples from mice inoculated with RML scrapie were collected at 30, 60, 90, 105, and 120 days post inoculation (dpi) or at the onset of clinical signs of disease (153 dpi). Retinal homogenates were tested for prion seeding activity. Antibody staining was used to assess accumulation of PrP Sc and the resulting response of retinal tissue. Loss of photoreceptors was used as a measure of neuronal death. PrP Sc seeding activity was first detected in all samples at 60 dpi. Accumulation of PrP Sc and coincident activation of retinal glia were first detected at 90 dpi. Activation of microglia was first detected at 105 dpi, but neuronal death was not detectable until 120 dpi. Our results demonstrate that by using the retina we can resolve the temporal separation between several key events in the pathogenesis of prion disease. Transmissible spongiform encephalopathies (TSEs) are a family of diseases caused by the accumulation of misfolded prion protein (PrP Sc ). 1 During progression of TSEs, like many protein misfolding disorders, transport of misfolded protein from one central nervous system (CNS) structure seeds protein misfolding and accumulation in another. 2 The details underlying this series of events that begins with the arrival of misfolded protein in a CNS structure and ends with neuronal death in that structure are not well understood. Seeding the brain with an inoculum of misfolded prion protein induces TSEs; thus, these diseases provide a unique opportunity to study the transport of PrP Sc from one CNS structure to another.Currently, there is no treatment for TSEs. Although in silico and in vitro approaches have been effective at identifying compounds with therapeutic potential, 3e8 development of effective therapies would be facilitated by a well-described in vivo model of misfolded protein transport and accumulation, with objective measures of neural degeneration.The retina is part of the CNS and is affected by numerous protein misfolding diseases, including Alzheimer disease, 9 Parkinson disease, 10e12 and numerous TSEs, including scrapie in sheep, 13,14 chronic wasting disease in

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Changes in Retinal Function and Morphology Are Early Clinical Signs of Disease in Cattle with Bovine Spongiform Encephalopathy

Cited by 19 publications

References 54 publications

Experimental Infection of Cattle With a Novel Prion Derived From Atypical H-Type Bovine Spongiform Encephalopathy

Experimental Infection of Cattle With a Novel Prion Derived From Atypical H-Type Bovine Spongiform Encephalopathy

Prion protein facilitates retinal iron uptake and is cleaved at the β-site: Implications for retinal iron homeostasis in prion disorders

Temporal Resolution of Misfolded Prion Protein Transport, Accumulation, Glial Activation, and Neuronal Death in the Retinas of Mice Inoculated with Scrapie

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