Transmissible spongiform encephalopathies are fatal neurodegenerative diseases caused by the conversion of prion protein (PrP(C)) into an infectious isoform (PrP(Sc)). How this event leads to pathology is not fully understood. Here we demonstrate that protein synthesis in neurons is enhanced via PrP(C) interaction with stress-inducible protein 1 (STI1). We also show that neuroprotection and neuritogenesis mediated by PrP(C)-STI1 engagement are dependent upon the increased protein synthesis mediated by PI3K-mTOR signaling. Strikingly, the translational stimulation mediated by PrP(C)-STI1 binding is corrupted in neuronal cell lines persistently infected with PrP(Sc), as well as in primary cultured hippocampal neurons acutely exposed to PrP(Sc). Consistent with this, high levels of eukaryotic translation initiation factor 2alpha (eIF2alpha) phosphorylation were found in PrP(Sc)-infected cells and in neurons acutely exposed to PrP(Sc). These data indicate that modulation of protein synthesis is critical for PrP(C)-STI1 neurotrophic functions, and point to the impairment of this process during PrP(Sc) infection as a possible contributor to neurodegeneration.

Chronic wasting disease (CWD) is a prion disease of captive and free-ranging deer (Odocoileus spp), elk (Cervus elaphus nelsonii) and moose (Alces alces shirasi). Unlike in most other prion disease...

Chronic wasting disease (CWD) is a fatal prion disease of wild and captive cervids in North America. Prions are infectious agents composed of a misfolded version of a host-encoded protein, termed PrP^Sc. Infected cervids excrete and secrete prions, contributing to lateral transmission. Geographical distribution is expanding and case numbers in wild cervids are increasing. Recently, the first European cases of CWD have been reported in a wild reindeer and two moose from Norway. Therefore, methods to detect the infection early in the incubation time using easily available samples are desirable to facilitate effective disease management. We have adapted the real-time quaking induced conversion (RT-QuIC) assay, a sensitive in vitro prion amplification method, for pre-clinical detection of prion seeding activity in elk feces. Testing fecal samples from orally inoculated elk taken at various time points post infection revealed early shedding and detectable prion seeding activity throughout the disease course. Early shedding was also found in two elk encoding a PrP genotype associated with reduced susceptibility for CWD. In summary, we suggest that detection of CWD prions in feces by RT-QuIC may become a useful tool to support CWD surveillance in wild and captive cervids. The finding of early shedding independent of the elk’s prion protein genotype raises the question whether prolonged survival is beneficial, considering accumulation of environmental prions and its contribution to CWD transmission upon extended duration of shedding.

Chronic wasting disease (CWD) is a prion disease found in both free-ranging and farmed cervids. Susceptibility of these animals to CWD is governed by various exogenous and endogenous factors. Past studies have demonstrated that polymorphisms within the prion protein (PrP) sequence itself affect an animal’s susceptibility to CWD. PrP polymorphisms can modulate CWD pathogenesis in two ways: the ability of the endogenous prion protein (PrP^C) to convert into infectious prions (PrP^Sc) or it can give rise to novel prion strains. In vivo studies in susceptible cervids, complemented by studies in transgenic mice expressing the corresponding cervid PrP sequence, show that each polymorphism has distinct effects on both PrP^C and PrP^Sc. It is not entirely clear how these polymorphisms are responsible for these effects, but in vitro studies suggest they play a role in modifying PrP epitopes crucial for PrP^C to PrP^Sc conversion and determining PrP^C stability. PrP polymorphisms are unique to one or two cervid species and most confer a certain degree of reduced susceptibility to CWD. However, to date, there are no reports of polymorphic cervid PrP alleles providing absolute resistance to CWD. Studies on polymorphisms have focused on those found in CWD-endemic areas, with the hope that understanding the role of an animal’s genetics in CWD can help to predict, contain, or prevent transmission of CWD.

Prions cause fatal neurodegenerative diseases in humans and animals by converting the cellular prion protein PrP C into aggregation-prone PrP Sc. Chronic wasting disease (CWD) is a prion disease or transmissible spongiform encephalopathy (TSE) of free-ranging and farmed cervids. CWD is highly contagious and transmitted through horizontal transmission enabled by the shedding of prions in excreta and their persistence in the environment. The disease is undergoing a dramatic spread across North America, has been found in South Korea, and, recently, has been identified for the first time in Europe in free-ranging reindeer (Rangifer tarandus tarandus) and moose in Norway. CWD CWD first appeared in North America in captive animals in 1969 when biologists conducting a physiological study recognized that their animals often died with a syndrome of weight loss and behavioral changes. The biologists thought that the animals were probably dying of a nutritional deficiency due to toxin exposure or stressful conditions of captivity. In 1978, histological examination of brains of affected deer from wildlife research facilities in Colorado and Wyoming, United States, allowed us, for the first time, to recognize TSE features and define CWD as such [1]. Since then, CWD has had an impressive expansion and a very rapid spread in North America; the geographic range of CWD includes 21 US states and 2 provinces in Canada (Saskatchewan and Alberta) and is most likely to continue to grow [2]. Disease prevalence in free-ranging deer can be as high as 40% in the most endemic areas in Colorado and Wyoming [3]. More recently, CWD has been described in Northern Europe [4]. CWD is a slowly developing disease, with prolonged incubation periods. Experimental inoculation of mule deer has confirmed a 2-to 4-year incubation time [3]. The disease has been found in yearling deer and elk as well as in adult animals as old as 15 years. Clinical symptoms include physical and behavioral changes [5]. All these symptoms can be subtle early in the disease or fall within the normal repertoire of behavior or seasonal body mass fluctuations. Therefore, diagnosis based on clinical signs is not reliable and pathological or biochemical analyses of brain or lymphatic tissue are necessary. These will reveal neuronal vacuolation and spongiform changes, astrocytosis, and PrP Sc accumulation in the brain or PrP Sc deposits in lymphoid tissues. In most prion diseases, PrP Sc and infectivity are restricted mainly to the brain. However, in CWD, PrP Sc can be found in many extraneural tissues, body fluids, and excreta, facilitating horizontal transmission.

Prions cause infectious and fatal neurodegenerative diseases in mammals. Chronic wasting disease (CWD), a prion disease of cervids, spreads efficiently among wild and farmed animals. Potential transmission to humans of CWD is a growing concern due to its increasing prevalence. Here, we provide evidence for a zoonotic potential of CWD prions, and its probable signature using mice expressing human prion protein (PrP) as an infection model. Inoculation of these mice with deer CWD isolates resulted in atypical clinical manifestation with prion seeding activity and efficient transmissible infectivity in the brain and, remarkably, in feces, but without classical neuropathological or Western blot appearances of prion diseases. Intriguingly, the protease-resistant PrP in the brain resembled that found in a familial human prion disease and was transmissible upon second passage. Our results suggest that CWD might infect humans, although the transmission barrier is likely higher compared to zoonotic transmission of cattle prions. Notably, our data suggest a different clinical presentation, prion signature, and tissue tropism, which causes challenges for detection by current diagnostic assays. Furthermore, the presence of infectious prions in feces is concerning because if this occurs in humans, it is a source for human-to-human transmission. These findings have strong implications for public health and CWD management.