Cellular prion protein localizes to the nucleus of endocrine and neuronal cells and interacts with structural chromatin components

Strom, Alexander; Wang, Gensheng; Picketts, David J.; Reimer, Rudolph; Stuke, Andreas W.; Scott, Fraser W.

doi:10.1016/j.ejcb.2010.11.015

Cited by 39 publications

(31 citation statements)

References 37 publications

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“…The possible mechanisms could be related to PrP C conformational changes in the M128V allele or the possible discrepancy between PrP C and PrP C M128V cell surface retention induced by Aβ oligomers. Although PrP C has been reported to be located in nuclear lamina of neuronal cells in the mice brain tissues and interact with histone H3, which suggests that PrP C may be involved in transcriptional regulation in the nucleus, 26 our preliminary data and most other studies 25,27 showed PrP C did not go into nucleus indicating that a direct influence of PrP C in the transcriptional regulation is unlikely.…”

Section: ■ Discussioncontrasting

confidence: 77%

Alzheimer’s Amyloid-β Oligomers Rescue Cellular Prion Protein Induced Tau Reduction via the Fyn Pathway

Chen

Chang

Lin

et al. 2013

ACS Chem. Neurosci.

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Amyloid-β (Aβ) and tau are the pathogenic hallmarks in Alzheimer's disease (AD). Aβ oligomers are considered the actual toxic entities, and the toxicity relies on the presence of tau. Recently, Aβ oligomers have been shown to specifically interact with cellular prion protein (PrP C ) where the role of PrP C in AD is still not fully understood. To investigate the downstream mechanism of PrP C and Aβ oligomer interaction and their possible relationships to tau, we examined tau expression in human neuroblastoma BE(2)-C cells transfected with murine PrP C and studied the effect under Aβ oligomer treatment. By Western blotting, we found that PrP C overexpression down-regulated tau protein and Aβ oligomer binding alleviated the tau reduction induced by wild type but not M128V PrP C , the high AD risk polymorphic allele in human prion gene. PrP C lacking the Aβ oligomer binding site was incapable of rescuing the level of tau reduction. Quantitative RT-PCR showed the PrP C effect was attributed to tau reduction at the transcription level. Treatment with Fyn pathway inhibitors, Fyn kinase inhibitor PP2 and MEK inhibitor U0126, reversed the PrP C -induced tau reduction and Aβ oligomer treatment modulated Fyn kinase activity. The results suggested Fyn pathway regulated Aβ−PrP C −tau signaling. Overall, our results demonstrated that PrP C down-regulated tau via the Fyn pathway and the effect can be regulated by Aβ oligomers. Our study facilitated the understanding of molecular mechanisms among PrP C , tau, and Aβ oligomers.

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Section: ■ Discussioncontrasting

confidence: 77%

Alzheimer’s Amyloid-β Oligomers Rescue Cellular Prion Protein Induced Tau Reduction via the Fyn Pathway

Chen

Chang

Lin

et al. 2013

ACS Chem. Neurosci.

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“…One of the unique characteristics of the abnormal prion protein (PrP Sc ) is its relative resistance to proteinase K-treatment resulting in a truncated molecule called PrP res [16], [17]. PrP C is expressed in a variety of tissues and cells [18]–[20] and is implicated in a wide range of cellular and physiological processes [21]–[26]. However, the exact physiological function of PrP C is still unclear.…”

Section: Introductionmentioning

confidence: 99%

Foodborne Transmission of Bovine Spongiform Encephalopathy to Non-Human Primates Results in Preclinical Rapid-Onset Obesity

et al. 2014

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Obesity has become one of the largest public health challenges worldwide. Recently, certain bacterial and viral pathogens have been implicated in the pathogenesis of obesity. In the present study, we retrospectively analyzed clinical data, plasma samples and post-mortem tissue specimens derived from a risk assessment study in bovine spongiform encephalopathy (BSE)-infected female cynomolgus monkeys (Macaca fascicularis). The original study design aimed to determine minimal infectious doses after oral or intracerebral (i.c.) infection of macaques to assess the risk for humans. High-dose exposures resulted in 100% attack rates and a median incubation time of 4.7 years as described previously. Retrospective analyses of clinical data from high-dosed macaques revealed that foodborne BSE transmission caused rapid weight gain within 1.5 years post infection (β = 0.915; P<0.0001) which was not seen in age- and sex-matched control animals or i.c. infected animals. The rapid-onset obesity was not associated with impaired pancreatic islet function or glucose metabolism. In the early preclinical phase of oral transmission associated with body weight gain, prion accumulation was confined to the gastrointestinal tract. Intriguingly, immunohistochemical findings suggest that foodborne BSE transmission has a pathophysiological impact on gut endocrine cells which may explain rapid weight gain. To our knowledge, this is the first experimental model which clearly demonstrates that foodborne pathogens can induce obesity.

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“…7 Although a nuclear localization of the prion protein had been reported in few studies, in particular in a human promyelocytic leukemia cell line 20 and in neuronal cells for both the protease-resistant PrP form in prion infected cells 21 and the normal PrP c in non-infected cells, 22 the role of this particular pool was not elucidated. An association of nuclear PrP c with histone H3 in neurones and b cells of the endocrine pancreas suggested a possible role of PrP c in transcriptional regulation, 23 but this hypothesis was not demonstrated definitely until our recent study in enterocytes. 9 Through a proteomic approach, we identified g-catenin, a component of desmosomes in differentiated cells, as a nuclear PrP c partner in proliferating intestinal epithelial cells.…”

Section: A Pool Of Prp C Is Targeted To the Nucleus Of Proliferative mentioning

confidence: 99%

The nucleo-junctional interplay of the cellular prion protein: A new partner in cancer-related signaling pathways?

Rousset

Leturque

Thenet

2016

Prion

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ABSTRACT. The cellular prion protein PrP c plays important roles in proliferation, cell death and survival, differentiation and adhesion. The participation of PrP c in tumor growth and metastasis was pointed out, but the underlying mechanisms were not deciphered completely. In the constantly renewing intestinal epithelium, our group demonstrated a dual localization of PrP c , which is targeted to cell-cell junctions in interaction with Src kinase and desmosomal proteins in differentiated enterocytes, but is predominantly nuclear in dividing cells. While the role of PrP c in the dynamics of intercellular junctions was confirmed in other biological systems, we unraveled its function in the nucleus only recently. We identified several nuclear PrP c partners, which comprise g-catenin, one of its desmosomal partners, b-catenin and TCF7L2, the main effectors of the canonical Wnt pathway, and YAP, one effector of the Hippo pathway. PrP c up-regulates the activity of the b-catenin/TCF7L2 complex and its invalidation impairs the proliferation of intestinal progenitors. We discuss how PrP c could participate to oncogenic processes through its interaction with Wnt and Hippo pathway effectors, which are controlled by cell-cell junctions and Src family kinases and dysregulated during tumorigenesis. This highlights new potential mechanisms that connect PrP c expression and subcellular redistribution to cancer.

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Cellular prion protein localizes to the nucleus of endocrine and neuronal cells and interacts with structural chromatin components

Cited by 39 publications

References 37 publications

Alzheimer’s Amyloid-β Oligomers Rescue Cellular Prion Protein Induced Tau Reduction via the Fyn Pathway

Alzheimer’s Amyloid-β Oligomers Rescue Cellular Prion Protein Induced Tau Reduction via the Fyn Pathway

Foodborne Transmission of Bovine Spongiform Encephalopathy to Non-Human Primates Results in Preclinical Rapid-Onset Obesity

The nucleo-junctional interplay of the cellular prion protein: A new partner in cancer-related signaling pathways?

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