Allelic Interference in Prion Replication Is Modulated by the Convertibility of the Interfering PrPC and Other Host-Specific Factors

ABSTRACT Early studies in transgenic mouse lines have shown that the coexpression of endogenous murine prion protein (PrPC) and transgenic PrPC from another species either inhibits or allows the propagation of prions, depending on the infecting prion strain and interacting protein species. The way whereby this phenomenon, so-called “interference,” is modulated remains to be determined. In this study, different transgenic mouse lines were crossbred to produce mice coexpressing bovine and porcine PrPC, bovine and murine PrPC, or murine and porcine PrPC. These animals and their respective hemizygous controls were inoculated with several prion strains from different sources (cattle, mice, and pigs) to examine the effects of the simultaneous presence of PrPC from two different species. Our results indicate interference with the infection process, manifested as extended survival times and reduced attack rates. The interference with the infectious process was reduced or absent when the potentiality interfering PrPC species was efficiently converted by the inoculated agent. However, the propagation of the endogenous murine PrPSc was favored, allowing us to speculate that host-specific factors may disturb the interference caused by the coexpression of an exogenous second PrPC. IMPORTANCE Prion propagation can be interfered with by the expression of a second prion protein in the host. In the present study, we investigated prion propagation in a host expressing two different prion protein genes. Our findings indicate that the ability of the second prion protein to interfere with prion propagation is related to the transmissibility of the prion in the host expressing only the interfering prion protein. The interference detected occurs in a prion strain-dependent manner. Interestingly, a bias favoring the propagation of the murine PrP allele has been observed. These results open the door to future studies in order to determine the role of host factors other than the PrP amino acid sequence in the interference in prion propagation.

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Orally Administered Amyloidophilic Compound Is Effective in Prolonging the Incubation Periods of Animals Cerebrally Infected with Prion Diseases in a Prion Strain-Dependent Manner

Journal of Virology ◽

10.1128/jvi.01563-07 ◽

2007 ◽

Vol 81 (23) ◽

pp. 12889-12898 ◽

Cited By ~ 71

Author(s):

Yuri Kawasaki ◽

Keiichi Kawagoe ◽

Chun-jen Chen ◽

Kenta Teruya ◽

Yuji Sakasegawa ◽

...

Keyword(s):

Prion Protein ◽

Therapeutic Efficacy ◽

Prion Diseases ◽

Neuroblastoma Cells ◽

Therapeutic Interventions ◽

Dependent Manner ◽

Cell Culture Study ◽

Prion Strain ◽

Incubation Periods ◽

Strain Dependent

ABSTRACT The establishment of effective therapeutic interventions for prion diseases is necessary. We report on a newly developed amyloidophilic compound that displays therapeutic efficacy when administered orally. This compound inhibited abnormal prion protein formation in prion-infected neuroblastoma cells in a prion strain-dependent manner: effectively for RML prion and marginally for 22L prion and Fukuoka-1 prion. When the highest dose (0.2% [wt/wt] in feed) was given orally to cerebrally RML prion-inoculated mice from inoculation until the terminal stage of disease, it extended the incubation periods by 2.3 times compared to the control. The compound exerted therapeutic efficacy in a prion strain-dependent manner such as that observed in the cell culture study: most effective for RML prion, less effective for 22L prion or Fukuoka-1 prion, and marginally effective for 263K prion. Its effectiveness depended on an earlier start of administration. The glycoform pattern of the abnormal prion protein in the treated mice was modified and showed predominance of the diglycosylated form, which resembled that of 263K prion, suggesting that diglycosylated forms of abnormal prion protein might be least sensitive or resistant to the compound. The mechanism of the prion strain-dependent effectiveness needs to be elucidated and managed. Nevertheless, the identification of an orally available amyloidophilic chemical encourages the pursuit of chemotherapy for prion diseases.

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Generation of inducible hepatitis C virus transgenic mouse lines

Zeitschrift für Gastroenterologie ◽

10.1055/s-2006-931743 ◽

2006 ◽

Vol 44 (01) ◽

Author(s):

E Ernst ◽

K Schönig ◽

H Bläker ◽

W Stremmel ◽

J Encke

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Transgenic Mouse ◽

Mouse Lines

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Necroptosis protects against exacerbation of acute pancreatitis

Cell Death and Disease ◽

10.1038/s41419-021-03847-w ◽

2021 ◽

Vol 12 (6) ◽

Author(s):

Michittra Boonchan ◽

Hideki Arimochi ◽

Kunihiro Otsuka ◽

Tomoko Kobayashi ◽

Hisanori Uehara ◽

...

Keyword(s):

Acute Pancreatitis ◽

Necrotizing Pancreatitis ◽

Neutrophil Infiltration ◽

Dependent Manner ◽

Protective Effects ◽

Interacting Protein ◽

Inflammatory Conditions ◽

Edematous Pancreatitis ◽

Genetic Deletion ◽

Dose Dependent

AbstractThe sensing of various extrinsic stimuli triggers the receptor-interacting protein kinase-3 (RIPK3)-mediated signaling pathway, which leads to mixed-lineage kinase-like (MLKL) phosphorylation followed by necroptosis. Although necroptosis is a form of cell death and is involved in inflammatory conditions, the roles of necroptosis in acute pancreatitis (AP) remain unclear. In the current study, we administered caerulein to Ripk3- or Mlkl-deficient mice (Ripk3−/− or Mlkl−/− mice, respectively) and assessed the roles of necroptosis in AP. We found that Ripk3−/− mice had significantly more severe pancreatic edema and inflammation associated with macrophage and neutrophil infiltration than control mice. Consistently, Mlkl−/− mice were more susceptible to caerulein-induced AP, which occurred in a time- and dose-dependent manner, than control mice. Mlkl−/− mice exhibit weight loss, edematous pancreatitis, necrotizing pancreatitis, and acinar cell dedifferentiation in response to tissue damage. Genetic deletion of Mlkl resulted in downregulation of the antiapoptotic genes Bclxl and Cflar in association with increases in the numbers of apoptotic cells, as detected by TUNEL assay. These findings suggest that RIPK3 and MLKL-mediated necroptosis exerts protective effects in AP and caution against the use of necroptosis inhibitors for AP treatment.

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Control of microtubule dynamics using an optogenetic microtubule plus end–F-actin cross-linker

The Journal of Cell Biology ◽

10.1083/jcb.201705190 ◽

2017 ◽

Vol 217 (2) ◽

pp. 779-793 ◽

Cited By ~ 9

Author(s):

Rebecca C. Adikes ◽

Ryan A. Hallett ◽

Brian F. Saway ◽

Brian Kuhlman ◽

Kevin C. Slep

Keyword(s):

Blue Light ◽

Actin Binding ◽

Cross Linking ◽

Dependent Manner ◽

Exclusion Zone ◽

Actin Networks ◽

Drosophila Melanogaster S2 Cells ◽

Actin Binding Domain ◽

Specific Factors ◽

Insight Into

We developed a novel optogenetic tool, SxIP–improved light-inducible dimer (iLID), to facilitate the reversible recruitment of factors to microtubule (MT) plus ends in an end-binding protein–dependent manner using blue light. We show that SxIP-iLID can track MT plus ends and recruit tgRFP-SspB upon blue light activation. We used this system to investigate the effects of cross-linking MT plus ends and F-actin in Drosophila melanogaster S2 cells to gain insight into spectraplakin function and mechanism. We show that SxIP-iLID can be used to temporally recruit an F-actin binding domain to MT plus ends and cross-link the MT and F-actin networks. Cross-linking decreases MT growth velocities and generates a peripheral MT exclusion zone. SxIP-iLID facilitates the general recruitment of specific factors to MT plus ends with temporal control enabling researchers to systematically regulate MT plus end dynamics and probe MT plus end function in many biological processes.

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Deletion of murine tau gene increases tau aggregation in a human mutant tau transgenic mouse model

Biochemical Society Transactions ◽

10.1042/bst0381001 ◽

2010 ◽

Vol 38 (4) ◽

pp. 1001-1005 ◽

Cited By ~ 14

Author(s):

Kunie Ando ◽

Karelle Leroy ◽

Céline Heraud ◽

Anna Kabova ◽

Zehra Yilmaz ◽

...

Keyword(s):

Mouse Model ◽

Transgenic Mouse ◽

Double Mutant ◽

Transgenic Mouse Model ◽

Tau Proteins ◽

Dependent Manner ◽

Age Dependent ◽

Ad Alzheimer’S Disease ◽

Tau Aggregation ◽

The Brain

We have reported previously a tau transgenic mouse model (Tg30tau) overexpressing human 4R1N double-mutant tau (P301S and G272V) and that develops AD (Alzheimer's disease)-like NFTs (neurofibrillary tangles) in an age-dependent manner. Since murine tau might interfere with the toxic effects of human mutant tau, we set out to analyse the phenotype of our Tg30tau model in the absence of endogenous murine tau with the aim to reproduce more faithfully a model of human tauopathy. By crossing the Tg30tau line with TauKO (tau-knockout) mice, we have obtained a new mouse line called Tg30×TauKO that expresses only exogenous human double-mutant 4R1N tau. Whereas Tg30×TauKO mice express fewer tau proteins compared with Tg30tau, they exhibit augmented sarkosyl-insoluble tau in the brain and an increased number of Gallyas-positive NFTs in the hippocampus. Taken together, exclusion of murine tau causes accelerated tau aggregation during aging of this mutant tau transgenic model.

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Expression and localization of androgen receptor-interacting protein-4 in the testis

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00287.2006 ◽

2007 ◽

Vol 292 (2) ◽

pp. E513-E522 ◽

Cited By ~ 6

Author(s):

Andrii Domanskyi ◽

Fu-Ping Zhang ◽

Mirja Nurmio ◽

Jorma J. Palvimo ◽

Jorma Toppari ◽

...

Keyword(s):

Androgen Receptor ◽

Sertoli Cell ◽

Germ Cells ◽

Sertoli Cells ◽

Hormone Receptor ◽

Luteinizing Hormone Receptor ◽

Dependent Manner ◽

Cell Nuclei ◽

Interacting Protein ◽

Independent Functions

Androgen receptor-interacting protein 4 (ARIP4) belongs to the SNF2 family of proteins involved in chromatin remodeling, DNA excision repair, and homologous recombination. It is a DNA-dependent ATPase, binds to DNA and mononucleosomes, and interacts with androgen receptor (AR) and modulates AR-dependent transactivation. We have examined in this study the expression and cellular localization of ARIP4 during postnatal development of mouse testis. ARIP4 was detected by immunohistochemistry in Sertoli cell nuclei at all ages studied, starting on day 5, and exhibited the highest expression level in adult mice. At the onset of spermatogenesis, ARIP4 expression became evident in spermatogonia, pachytene, and diplotene spermatocytes. Immunoreactive ARIP4 antigen was present in Leydig cell nuclei. In Sertoli cells ARIP4 was expressed in a stage-dependent manner, with high expression levels at stages II–VI and VII–VIII. ARIP4 expression patterns did not differ significantly in testes of wild-type, follicle-stimulating hormone receptor knockout, and luteinizing hormone receptor knockout mice. In testes of hypogonadal mice, ARIP4 was found mainly in interstitial cells and exhibited lower expression in Sertoli and germ cells. In vitro stimulation of rat seminiferous tubule segments with testosterone, FSH, or forskolin did not significantly change stage-specific levels of ARIP4 mRNA. Heterozygous ARIP4+/− mice were haploinsufficient and had reduced levels of Sertoli-cell specific androgen-regulated Rhox5 (also called Pem) mRNA. Collectively, ARIP4 is an AR coregulator in Sertoli cells in vivo, but the expression in the germ cells implies that it has also AR-independent functions in spermatogenesis.

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Nizp1, a Novel Multitype Zinc Finger Protein That Interacts with the NSD1 Histone Lysine Methyltransferase through a Unique C2HR Motif

Molecular and Cellular Biology ◽

10.1128/mcb.24.12.5184-5196.2004 ◽

2004 ◽

Vol 24 (12) ◽

pp. 5184-5196 ◽

Cited By ~ 35

Author(s):

Anders Lade Nielsen ◽

Poul Jørgensen ◽

Thierry Lerouge ◽

Margarita Cerviño ◽

Pierre Chambon ◽

...

Keyword(s):

Rna Polymerase Ii ◽

Zinc Finger ◽

Zinc Finger Protein ◽

Sotos Syndrome ◽

Dependent Manner ◽

Interacting Protein ◽

Protein Protein Interaction ◽

Histone Lysine ◽

Histone Lysine Methyltransferase ◽

Lysine Methyltransferase

ABSTRACT Haploinsufficiency of the NSD1 gene is a hallmark of Sotos syndrome, and rearrangements of this gene by translocation can cause acute myeloid leukemia. The NSD1 gene product is a SET-domain histone lysine methyltransferase that has previously been shown to interact with nuclear receptors. We describe here a novel NSD1-interacting protein, Nizp1, that contains a SCAN box, a KRAB-A domain, and four consensus C2H2-type zinc fingers preceded by a unique finger derivative, referred to herein as the C2HR motif. The C2HR motif functions to mediate protein-protein interaction with the cysteine-rich (C5HCH) domain of NSD1 in a Zn(II)-dependent fashion, and when tethered to RNA polymerase II promoters, represses transcription in an NSD1-dependent manner. Mutations of the cysteine or histidine residues in the C2HR motif abolish the interaction of Nizp1 with NSD1 and compromise the ability of Nizp1 to repress transcription. Interestingly, converting the C2HR motif into a canonical C2H2 zinc finger has a similar effect. Thus, Nizp1 contains a novel type of zinc finger motif that functions as a docking site for NSD1 and is more than just a degenerate evolutionary remnant of a C2H2 motif.

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High Glucose and Lipopolysaccharide Prime NLRP3 Inflammasome via ROS/TXNIP Pathway in Mesangial Cells

Journal of Diabetes Research ◽

10.1155/2016/6973175 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 48

Author(s):

Hong Feng ◽

Junling Gu ◽

Fang Gou ◽

Wei Huang ◽

Chenlin Gao ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Nlrp3 Inflammasome ◽

High Glucose ◽

Mesangial Cells ◽

Central Component ◽

Dependent Manner ◽

Glomerular Mesangial Cells ◽

Interacting Protein

While inflammation is considered a central component in the development in diabetic nephropathy, the mechanism remains unclear. The NLRP3 inflammasome acts as both a sensor and a regulator of the inflammatory response. The NLRP3 inflammasome responds to exogenous and endogenous danger signals, resulting in cleavage of procaspase-1 and activation of cytokines IL-1β, IL-18, and IL-33, ultimately triggering an inflammatory cascade reaction. This study observed the expression of NLRP3 inflammasome signaling stimulated by high glucose, lipopolysaccharide, and reactive oxygen species (ROS) inhibitor N-acetyl-L-cysteine in glomerular mesangial cells, aiming to elucidate the mechanism by which the NLRP3 inflammasome signaling pathway may contribute to diabetic nephropathy. We found that the expression of thioredoxin-interacting protein (TXNIP), NLRP3, and IL-1βwas observed by immunohistochemistry in vivo. Simultaneously, the mRNA and protein levels of TXNIP, NLRP3, procaspase-1, and IL-1βwere significantly induced by high glucose concentration and lipopolysaccharide in a dose-dependent and time-dependent manner in vitro. This induction by both high glucose and lipopolysaccharide was significantly inhibited by N-acetyl-L-cysteine. Our results firstly reveal that high glucose and lipopolysaccharide activate ROS/TXNIP/ NLRP3/IL-1βinflammasome signaling in glomerular mesangial cells, suggesting a mechanism by which inflammation may contribute to the development of diabetic nephropathy.

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