Generation of goats lacking prion protein

Yu, Guohua; Chen, Jianquan; Xu, Yuanyuan; Zhu, Chuanbing; Yu, Hai; Liu, Siguo; Sha, Hao; Chen, Juan; Xu, Xujun; Wu, Youbing; Zhang, Aimin; Ma, Jiyan; Cheng, Guangcun

doi:10.1002/mrd.20960

Cited by 51 publications

(35 citation statements)

References 3 publications

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“…Whilst no in-depth phenotypic description of the PrP C -null goats has been published, the animals in question were reported to be healthy up to at least 5 months of age (Yu et al, 2009; Zhu et al, 2009). Similarly, detailed clinical and histopathological examinations in addition to analyses of blood samples and isolated peripheral blood lymphocytes uncovered no overt abnormalities of PrP C -null cattle (Richt et al, 2007).…”

Section: Animal Models For Investigating Prpc Functionmentioning

confidence: 99%

Physiological Functions of the Cellular Prion Protein

Castle

Gill

2017

Front. Mol. Biosci.

168

157

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The prion protein, PrPC, is a small, cell-surface glycoprotein notable primarily for its critical role in pathogenesis of the neurodegenerative disorders known as prion diseases. A hallmark of prion diseases is the conversion of PrPC into an abnormally folded isoform, which provides a template for further pathogenic conversion of PrPC, allowing disease to spread from cell to cell and, in some circumstances, to transfer to a new host. In addition to the putative neurotoxicity caused by the misfolded form(s), loss of normal PrPC function could be an integral part of the neurodegenerative processes and, consequently, significant research efforts have been directed toward determining the physiological functions of PrPC. In this review, we first summarise important aspects of the biochemistry of PrPC before moving on to address the current understanding of the various proposed functions of the protein, including details of the underlying molecular mechanisms potentially involved in these functions. Over years of study, PrPC has been associated with a wide array of different cellular processes and many interacting partners have been suggested. However, recent studies have cast doubt on the previously well-established links between PrPC and processes such as stress-protection, copper homeostasis and neuronal excitability. Instead, the functions best-supported by the current literature include regulation of myelin maintenance and of processes linked to cellular differentiation, including proliferation, adhesion, and control of cell morphology. Intriguing connections have also been made between PrPC and the modulation of circadian rhythm, glucose homeostasis, immune function and cellular iron uptake, all of which warrant further investigation.

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Section: Animal Models For Investigating Prpc Functionmentioning

confidence: 99%

Physiological Functions of the Cellular Prion Protein

Castle

Gill

2017

Front. Mol. Biosci.

168

157

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“…Even though gene knockouts using somatic nuclear transfer have been reported, these are long lasting and far from routine procedures (three reports so far in goats (Yu et al 2009), pigs (Fujimura et al 2008) and cows (Sendai et al 2006)). Nonetheless, alternative approaches can be used, including molecular profiling studies.…”

Section: Introductionmentioning

confidence: 99%

A small set of extra-embryonic genes defines a new landmark for bovine embryo staging

Degrelle¹,

Cao²,

Heyman³

et al. 2011

Reproduction

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Axis specification in mouse is determined by a sequence of reciprocal interactions between embryonic and extra-embryonic tissues so that a few extra-embryonic genes appear as 'patterning' the embryo. Considering these interactions as essential, but lacking in most mammals the genetically driven approaches used in mouse and the corresponding patterning mutants, we examined whether a molecular signature originating from extra-embryonic tissues could relate to the developmental stage of the embryo proper and predict it. To this end, we have profiled bovine extra-embryonic tissues at peri-implantation stages, when gastrulation and early neurulation occur, and analysed the subsequent expression profiles through the use of predictive methods as previously reported for tumour classification. A set of six genes (CALM1, CPA3, CITED1, DLD, HNRNPDL, and TGFB3), half of which had not been previously associated with any extra-embryonic feature, appeared significantly discriminative and mainly dependent on embryonic tissues for its faithful expression. The predictive value of this set of genes for gastrulation and early neurulation stages, as assessed on naive samples, was remarkably high (93%). In silico connected to the bovine orthologues of the mouse patterning genes, this gene set is proposed as a new trait for embryo staging. As such, this will allow saving the bovine embryo proper for molecular or cellular studies. To us, it offers as well new perspectives for developmental phenotyping and modelling of embryonic/extra-embryonic co-differentiation.

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“…The function of PrP is still unknown as evidenced by the plethora of seemingly unrelated proposals (24,25). Mice, cattle, and goats harboring a knocked-out PrP gene develop normally and do not present behavioral abnormalities (26)(27)(28)(29), although a role for PrP in myelination and neuroprotection in ischemic brain injury has been described (25,30). Conditional PrP knockout during adulthood did not lead to deleterious consequences, showing that PrP dispensability does not require compensatory mechanisms taking place during development (22,31).…”

mentioning

confidence: 99%

Unique drug screening approach for prion diseases identifies tacrolimus and astemizole as antiprion agents

Karapetyan

Sferrazza

Zhou

et al. 2013

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

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Prion diseases such as Creutzfeldt-Jakob disease (CJD) are incurable and rapidly fatal neurodegenerative diseases. Because prion protein (PrP) is necessary for prion replication but dispensable for the host, we developed the PrP-FRET-enabled high throughput assay (PrP-FEHTA) to screen for compounds that decrease PrP expression. We screened a collection of drugs approved for human use and identified astemizole and tacrolimus, which reduced cell-surface PrP and inhibited prion replication in neuroblastoma cells. Tacrolimus reduced total cellular PrP levels by a nontranscriptional mechanism. Astemizole stimulated autophagy, a hitherto unreported mode of action for this pharmacophore. Astemizole, but not tacrolimus, prolonged the survival time of prion-infected mice. Astemizole is used in humans to treat seasonal allergic rhinitis in a chronic setting. Given the absence of any treatment option for CJD patients and the favorable drug characteristics of astemizole, including its ability to cross the bloodbrain barrier, it may be considered as therapy for CJD patients and for prophylactic use in familial prion diseases. Importantly, our results validate PrP-FEHTA as a method to identify antiprion compounds and, more generally, FEHTA as a unique drug discovery platform.protein misfolding | high-throughput screening | prion therapeutics

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Generation of goats lacking prion protein

Cited by 51 publications

References 3 publications

Physiological Functions of the Cellular Prion Protein

Physiological Functions of the Cellular Prion Protein

A small set of extra-embryonic genes defines a new landmark for bovine embryo staging

Unique drug screening approach for prion diseases identifies tacrolimus and astemizole as antiprion agents

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