Prion dementia without characteristic pathology

Collinge, John; Owen, F.; Poulter, Mark; Leach, M.; Crow, Timothy J.; Rossor, Martin N.; Hardy, John; Mullan, Michael; Janota, I.; Lantos, Peter L.

doi:10.1016/0140-6736(90)91518-f

Cited by 218 publications

(84 citation statements)

References 31 publications

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“…Burrowing of food in the home cage was found to be inversely proportional to disease progression in scrapie inoculated mice. Consistent with other studies there was a decline in spontaneous alternation, beginning around 10 weeks post inoculation and there was a statistically significant reduction in glucose consumption in scrapie inoculated mice during weeks [15][16][17][18][19]. A statistically significant effect of group was also observed in the horizontal bar test, which tests motor coordination [84].…”

Section: Behavior Assays Used In Mouse Models Of Prion Diseasesupporting

confidence: 76%

“…This is most dramatically represented in subclinical prion disease (i.e., measurable CNS PrP Sc without clinical disease) and in prion-infected animals demonstrating significant clinical disease but lacking detectable PrP Sc [7,18,19]. This lack of correlation between patterns of brain PrP Sc deposition and clinical disease is well documented in many natural and experimentally infected TSE affected animals, including TSE-infected cattle, goats, and mice [18,[20][21][22].…”

Section: Introductionmentioning

confidence: 99%

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Neurobehavioral Testing in Prion Disease Studies

Seelig¹,

Benneyworth²,

Bryant³

2017

Prion - An Overview

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The prion diseases are neurodegenerative diseases characterized by progressive neurocognitive decline and terminal dementia. In this review, we will discuss the role of neurobehavioral testing in mammalian prion disease model systems, including (1) a review of the clinical phenotype of the major prion diseases in natural disease, (2) an evidence-based summary of the benefits and shortcomings of commonly used behavioral assays, and (3) a review of the neurobehavioral testing in rodent prion models. Based upon this review, and in light of the established importance of model systems in studies of prion pathogenesis and the proven role of behavioral testing in nonprion disease neurodegenerative diseases, it is vital that prion researchers consider the clinical consequences of prion infection so as to maximize the impact of their work.

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Section: Behavior Assays Used In Mouse Models Of Prion Diseasesupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Neurobehavioral Testing in Prion Disease Studies

Seelig¹,

Benneyworth²,

Bryant³

2017

Prion - An Overview

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“…In scrapie, it is not yet clear whether a loss of function of PrP c or a gain of function by PrP sc is responsible for the neuronal loss and spongiform changes in the brain. However, the observation that clinical symptoms occur without any obvious scrapie deposits (Collinge et al, 1990;Medori et al, 1992) suggests that it is the loss of normal PrP c function, not the formation of PrP sc deposits, that causes prion disease (Aguzzi et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Clathrin-independent internalization of normal cellular prion protein in neuroblastoma cells is associated with the Arf6 pathway

Kang

Zhao

Lovaas

et al. 2009

Journal of Cell Science

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To understand the role of clathrin-mediated endocytosis in the internalization of normal cellular prion protein (PrPc) in neuronal cells, N2a cells were depleted of clathrin by RNA interference. PrPc internalization via the constitutive endocytic pathway in the absence of Cu2+ and the stimulated pathway in the presence of Cu2+ were measured in both control and clathrin-depleted cells. Depletion of clathrin had almost no effect on the internalization of PrPc either in the presence or absence of Cu2+, in contrast to the marked reduction observed in transferrin uptake. By contrast, the internalization of PrPc was inhibited by the raft-disrupting drugs filipin and nystatin, and by the dominant-negative dynamin-1 mutant dynamin-1 K44A, both in the presence and absence of Cu2+. The internalized PrPc was found to colocalize with cargo that traffic in the Arf6 pathway and in large vacuoles in cells expressing the Arf6 dominant-active mutant. These results show that PrPc is internalized in a clathrin-independent pathway that is associated with Arf6.

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“…There have been numerous models proposed for the neuronal cell loss and spongiform changes in the brain that occur in scrapie, but it is still not clear whether this pathology is due to a loss of functional PrP C or only to a gain of function by PrP Sc . Clinical symptoms can occur without any obvious scrapie deposits (Collinge et al, 1990;Medori et al, 1992), which has led to the suggestion that the loss of normal PrP C function, not formation of PrP Sc deposits, causes prion disease (Aguzzi and Weissmann, 1997). Unfortunately, the normal function of PrP C is unknown, although its conservation in many different species suggests that it plays a prominent role in a basic physiological process.…”

Section: Introductionmentioning

confidence: 99%

Cellular prion protein (PrPC) protects neuronal cells from the effect of huntingtin aggregation

Lee

Panzera

Rogawski

et al. 2007

Journal of Cell Science

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The effect of normal cellular prion protein (PrPC) on abnormal protein aggregation was examined by transfecting huntingtin fragments (Htt) into SN56 neuronal-derived cells depleted of PrPC by RNA interference. PrPC depletion caused an increase in both the number of cells containing granules and the number of apoptotic cells. Consistent with the increase in Htt aggregation, PrPC depletion caused an decrease in proteasome activity and a decrease in the activities of cellular defense enzymes compared with control cells whereas reactive oxygen species (ROS) increased more than threefold. Therefore, PrPC may protect against Htt toxicity in neuronal cells by increasing cellular defense proteins, decreasing ROS and increasing proteasome activity thereby increasing Htt degradation. Depletion of endogenous PrPC in non-neuronal Caco-2 and HT-29 cells did not affect ROS levels or proteasome activity suggesting that only in neuronal cells does PrPC confer protection against Htt toxicity. The protective effect of PrPC was further evident in that overexpression of mouse PrPC in SN56 cells transfected with Htt caused a decrease in both the number of cells with Htt granules and the number of apoptotic cells, whereas there was no effect of PrPC expression in non-neuronal NIH3T3 or CHO cells. Finally, in chronically scrapie (PrPSc)-infected cells, ROS increased more than twofold while proteasome activity was decreased compared to control cells. Although this could be a direct effect of PrPSc, it is also possible that, since PrPC specifically prevents pathological protein aggregation in neuronal cells, partial loss of PrPC itself increases PrPSc aggregation.

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Prion dementia without characteristic pathology

Cited by 218 publications

References 31 publications

Neurobehavioral Testing in Prion Disease Studies

Neurobehavioral Testing in Prion Disease Studies

Clathrin-independent internalization of normal cellular prion protein in neuroblastoma cells is associated with the Arf6 pathway

Cellular prion protein (PrPC) protects neuronal cells from the effect of huntingtin aggregation

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