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Article ; Online: Cerebral organoids as a new model for prion disease.

Groveman, Bradley R / Smith, Anna / Williams, Katie / Haigh, Cathryn L

2021 Volume 17, Issue 7, Page(s) e1009747

MeSH term(s)	Brain ; Humans ; Organoids ; Prion Diseases
Language	English
Publishing date	2021-07-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Review
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7366
ISSN (online)	1553-7374
ISSN	1553-7366
DOI	10.1371/journal.ppat.1009747
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Sporadic Creutzfeldt-Jakob disease infected human cerebral organoids retain the original human brain subtype features following transmission to humanized transgenic mice.

Groveman, Bradley R / Race, Brent / Foliaki, Simote T / Williams, Katie / Hughson, Andrew G / Baune, Chase / Zanusso, Gianluigi / Haigh, Cathryn L

Acta neuropathologica communications

2023 Volume 11, Issue 1, Page(s) 28

Abstract: Human cerebral organoids (COs) are three-dimensional self-organizing cultures of cerebral brain tissue differentiated from induced pluripotent stem cells. We have recently shown that COs are susceptible to infection with different subtypes of Creutzfeldt- ...

Abstract	Human cerebral organoids (COs) are three-dimensional self-organizing cultures of cerebral brain tissue differentiated from induced pluripotent stem cells. We have recently shown that COs are susceptible to infection with different subtypes of Creutzfeldt-Jakob disease (CJD) prions, which in humans cause different manifestations of the disease. The ability to study live human brain tissue infected with different CJD subtypes opens a wide array of possibilities from differentiating mechanisms of cell death and identifying neuronal selective vulnerabilities to testing therapeutics. However, the question remained as to whether the prions generated in the CO model truly represent those in the infecting inoculum. Mouse models expressing human prion protein are commonly used to characterize human prion disease as they reproduce many of the molecular and clinical phenotypes associated with CJD subtypes. We therefore inoculated these mice with COs that had been infected with two CJD subtypes (MV1 and MV2) to see if the original subtype characteristics (referred to as strains once transmitted into a model organism) of the infecting prions were maintained in the COs when compared with the original human brain inocula. We found that disease characteristics caused by the molecular subtype of the disease associated prion protein were similar in mice inoculated with either CO derived material or human brain material, demonstrating that the disease associated prions generated in COs shared strain characteristics with those in humans. As the first and only in vitro model of human neurodegenerative disease that can faithfully reproduce different subtypes of prion disease, these findings support the use of the CO model for investigating human prion diseases and their subtypes.
MeSH term(s)	Humans ; Mice ; Animals ; Creutzfeldt-Jakob Syndrome/metabolism ; Mice, Transgenic ; Prion Proteins/genetics ; Prion Proteins/metabolism ; Neurodegenerative Diseases/metabolism ; Brain/metabolism ; Prions/metabolism ; Prion Diseases/metabolism ; Organoids/metabolism
Chemical Substances	Prion Proteins ; Prions
Language	English
Publishing date	2023-02-14
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-023-01512-1
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Article ; Online: Temporary alteration of neuronal network communication is a protective response to redox imbalance that requires GPI-anchored prion protein.

Foliaki, Simote T / Wood, Aleksandar / Williams, Katie / Smith, Anna / Walters, Ryan O / Baune, Chase / Groveman, Bradley R / Haigh, Cathryn L

Redox biology

2023 Volume 63, Page(s) 102733

Abstract: Cellular prion protein ( ... ...

Abstract	Cellular prion protein (PrP
MeSH term(s)	Mice ; Animals ; Prion Proteins/genetics ; Prion Proteins/metabolism ; Prions/metabolism ; Synaptic Transmission ; Neurons/metabolism ; Disease Models, Animal ; Oxidation-Reduction ; Prion Diseases
Chemical Substances	Prion Proteins ; Prions
Language	English
Publishing date	2023-05-05
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2701011-9
ISSN	2213-2317 ; 2213-2317
ISSN (online)	2213-2317
ISSN	2213-2317
DOI	10.1016/j.redox.2023.102733
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Article ; Online: A PrP EGFR signaling axis controls neural stem cell senescence through modulating cellular energy pathways.

Groveman, Bradley R / Schwarz, Benjamin / Bohrnsen, Eric / Foliaki, Simote T / Carroll, James A / Wood, Aleksandar R / Bosio, Catharine M / Haigh, Cathryn L

The Journal of biological chemistry

2023 Volume 299, Issue 11, Page(s) 105319

Abstract: Mis-folding of the prion protein (PrP) is known to cause neurodegenerative disease; however, the native function of this protein remains poorly defined. PrP has been linked with many cellular functions, including cellular proliferation and senescence. It ...

Abstract	Mis-folding of the prion protein (PrP) is known to cause neurodegenerative disease; however, the native function of this protein remains poorly defined. PrP has been linked with many cellular functions, including cellular proliferation and senescence. It is also known to influence epidermal growth factor receptor (EGFR) signaling, a pathway that is itself linked with both cell growth and senescence. Adult neural stem cells (NSCs) persist at low levels in the brain throughout life and retain the ability to proliferate and differentiate into new neural lineage cells. KO of PrP has previously been shown to reduce NSC proliferative capacity. We used PrP KO and WT NSCs from adult mouse brain to examine the influence of PrP on cellular senescence, EGFR signaling, and the downstream cellular processes. PrP KO NSCs showed decreased cell proliferation and increased senescence in in vitro cultures. Expression of EGFR was decreased in PrP KO NSCs compared with WT NSCs and additional supplementation of EGF was sufficient to reduce senescence. RNA-seq analysis confirmed that significant changes were occurring at the mRNA level within the EGFR signaling pathway and these were associated with reduced expression of mitochondrial components and correspondingly reduced mitochondrial function. Metabolomic analysis of cellular energy pathways showed that blockages were occurring at critical sites for production of energy and biomass, including catabolism of pyruvate. We conclude that, in the absence of PrP, NSC growth pathways are downregulated as a consequence of insufficient energy and growth intermediates.
MeSH term(s)	Animals ; Mice ; Cell Proliferation ; Cellular Senescence ; ErbB Receptors/genetics ; ErbB Receptors/metabolism ; Neural Stem Cells/metabolism ; Neurodegenerative Diseases/metabolism ; Prion Proteins/genetics ; Prion Proteins/metabolism ; Prions/metabolism ; Signal Transduction/genetics ; Mice, Inbred C57BL
Chemical Substances	ErbB Receptors (EC 2.7.10.1) ; Prion Proteins ; Prions
Language	English
Publishing date	2023-10-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2023.105319
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Article ; Online: Efficacy of Wex-cide 128 disinfectant against multiple prion strains.

Baune, Chase / Groveman, Bradley R / Hughson, Andrew G / Thomas, Tina / Twardoski, Barry / Priola, Suzette / Chesebro, Bruce / Race, Brent

PloS one

2023 Volume 18, Issue 8, Page(s) e0290325

Abstract: Prion diseases are transmissible, fatal neurologic diseases that include Creutzfeldt-Jakob Disease (CJD) in humans, chronic wasting disease (CWD) in cervids, bovine spongiform encephalopathy (BSE) in cattle and scrapie in sheep. Prions are extremely ... ...

Abstract	Prion diseases are transmissible, fatal neurologic diseases that include Creutzfeldt-Jakob Disease (CJD) in humans, chronic wasting disease (CWD) in cervids, bovine spongiform encephalopathy (BSE) in cattle and scrapie in sheep. Prions are extremely difficult to inactivate and established methods to reduce prion infectivity are often dangerous, caustic, expensive, or impractical. Identifying viable and safe methods for treating prion contaminated materials is important for hospitals, research facilities, biologists, hunters, and meat-processors. For three decades, some prion researchers have used a phenolic product called Environ LpH (eLpH) to inactivate prions. ELpH has been discontinued, but a similar product, Wex-cide 128, containing the similar phenolic chemicals as eLpH is now available. In the current study, we directly compared the anti-prion efficacy of eLpH and Wex-cide 128 against prions from four different species (hamster 263K, cervid CWD, mouse 22L and human CJD). Decontamination was performed on either prion infected brain homogenates or prion contaminated steel wires and mouse bioassay was used to quantify the remaining prion infectivity. Our data show that both eLpH and Wex-cide 128 removed 4.0-5.5 logs of prion infectivity from 22L, CWD and 263K prion homogenates, but only about 1.25-1.50 logs of prion infectivity from human sporadic CJD. Wex-cide 128 is a viable substitute for inactivation of most prions from most species, but the resistance of CJD to phenolic inactivation is a concern and emphasizes the fact that inactivation methods should be confirmed for each target prion strain.
MeSH term(s)	Cricetinae ; Humans ; Animals ; Cattle ; Mice ; Sheep ; Prions ; Creutzfeldt-Jakob Syndrome ; Scrapie ; Brain ; Deer ; Disinfectants/pharmacology ; Phenols ; Sprains and Strains
Chemical Substances	Prions ; Disinfectants ; Phenols
Language	English
Publishing date	2023-08-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0290325
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Article ; Online: Neural cell engraftment therapy for sporadic Creutzfeldt-Jakob disease restores neuroelectrophysiological parameters in a cerebral organoid model.

Williams, Katie / Foliaki, Simote T / Race, Brent / Smith, Anna / Thomas, Tina / Groveman, Bradley R / Haigh, Cathryn L

Stem cell research & therapy

2023 Volume 14, Issue 1, Page(s) 348

Abstract: Background: Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is a fatal neurodegenerative disease with currently no treatment options. Stem cell therapy for neurodegenerative diseases is emerging as a possible treatment ... ...

Abstract	Background: Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is a fatal neurodegenerative disease with currently no treatment options. Stem cell therapy for neurodegenerative diseases is emerging as a possible treatment option. However, while there are a few clinical trials for other neurodegenerative disorders such as Parkinson's disease, prion disease cell therapy research has so far been confined to animal models. Methods: Here, we use a novel approach to study cell therapies in sCJD using a human cerebral organoid model. Cerebral organoids can be infected with sCJD prions allowing us to assess how neural precursor cell (NPC) therapy impacts the progression of sCJD. After 90 days of sCJD or mock infection, organoids were either seeded with NPCs or left unseeded and monitored for cellular composition changes, prion infection parameters and neuroelectrophysiological function at 180 days post-infection. Results: Our results showed NPCs integrated into organoids leading to an increase in neuronal markers and changes in cell signaling irrespective of sCJD infection. Although a small, but significant, decrease in protease-resistant PrP deposition was observed in the CJD-infected organoids that received the NPCs, other disease-associated parameters showed minimal changes. However, the NPCs had a beneficial impact on organoid function following infection. sCJD infection caused reduction in neuronal spike rate and mean burst spike rate, indicative of reduced action potentials. NPC seeding restored these electrophysiological parameters to the uninfected control level. Conclusions: Together with the previous animal studies, our results support that cell therapy may have some functional benefit for the treatment of human prion diseases.
MeSH term(s)	Animals ; Humans ; Creutzfeldt-Jakob Syndrome/therapy ; Neurodegenerative Diseases ; Prions ; Prion Diseases ; Organoids
Chemical Substances	Prions
Language	English
Publishing date	2023-12-05
Publishing country	England
Document type	Journal Article
ZDB-ID	2548671-8
ISSN	1757-6512 ; 1757-6512
ISSN (online)	1757-6512
ISSN	1757-6512
DOI	10.1186/s13287-023-03591-2
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Article: Using our mini-brains: cerebral organoids as an improved cellular model for human prion disease.

Groveman, Bradley R / Walters, Ryan / Haigh, Cathryn L

Neural regeneration research

2019 Volume 15, Issue 6, Page(s) 1019–1020

Language	English
Publishing date	2019-12-11
Publishing country	India
Document type	Journal Article ; Review
ZDB-ID	2388460-5
ISSN	1876-7958 ; 1673-5374
ISSN (online)	1876-7958
ISSN	1673-5374
DOI	10.4103/1673-5374.270300
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Article ; Online: Sensitive detection of pathological seeds of α-synuclein, tau and prion protein on solid surfaces.

Orrú, Christina D / Groveman, Bradley R / Hughson, Andrew G / Barrio, Tomás / Isiofia, Kachi / Race, Brent / Ferreira, Natalia C / Gambetti, Pierluigi / Schneider, David A / Masujin, Kentaro / Miyazawa, Kohtaro / Ghetti, Bernardino / Zanusso, Gianluigi / Caughey, Byron

PLoS pathogens

2024 Volume 20, Issue 4, Page(s) e1012175

Abstract: Prions or prion-like aggregates such as those composed of PrP, α-synuclein, and tau are key features of proteinopathies such as prion, Parkinson's and Alzheimer's diseases, respectively. Their presence on solid surfaces may be biohazardous under some ... ...

Abstract	Prions or prion-like aggregates such as those composed of PrP, α-synuclein, and tau are key features of proteinopathies such as prion, Parkinson's and Alzheimer's diseases, respectively. Their presence on solid surfaces may be biohazardous under some circumstances. PrP prions bound to solids are detectable by ultrasensitive real-time quaking-induced conversion (RT-QuIC) assays if the solids can be immersed in assay wells or the prions transferred to pads. Here we show that prion-like seeds can remain detectable on steel wires for at least a year, or even after enzymatic cleaning and sterilization. We also show that contamination of larger objects with pathological seeds of α-synuclein, tau, and PrP can be detected by simply assaying a sampling medium that has been transiently applied to the surface. Human α-synuclein seeds in dementia with Lewy bodies brain tissue were detected by α-synuclein RT-QuIC after drying of tissue dilutions with concentrations as low as 10-6 onto stainless steel. Tau RT-QuIC detected tau seeding activity on steel exposed to Alzheimer's disease brain tissue diluted as much as a billion fold. Prion RT-QuIC assays detected seeding activity on plates exposed to brain dilutions as extreme as 10-5-10-8 from prion-affected humans, sheep, cattle and cervids. Sampling medium collected from surgical instruments used in necropsies of sporadic Creutzfeldt-Jakob disease-infected transgenic mice was positive down to 10-6 dilution. Sensitivity for prion detection was not sacrificed by omitting the recombinant PrP substrate from the sampling medium during its application to a surface and subsequent storage as long as the substrate was added prior to performing the assay reaction. Our findings demonstrate practical prototypic surface RT-QuIC protocols for the highly sensitive detection of pathologic seeds of α-synuclein, tau, and PrP on solid objects.
MeSH term(s)	tau Proteins/metabolism ; alpha-Synuclein/metabolism ; alpha-Synuclein/analysis ; Humans ; Prion Proteins/metabolism ; Animals ; Mice ; Brain/metabolism ; Brain/pathology ; Prions/metabolism ; Lewy Body Disease/metabolism
Chemical Substances	tau Proteins ; alpha-Synuclein ; Prion Proteins ; Prions
Language	English
Publishing date	2024-04-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1012175
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Article ; Online: Reduced SOD2 expression does not influence prion disease course or pathology in mice.

Foliaki, Simote T / Race, Brent / Williams, Katie / Baune, Chase / Groveman, Bradley R / Haigh, Cathryn L

PloS one

2021 Volume 16, Issue 11, Page(s) e0259597

Abstract: Prion diseases are progressive, neurodegenerative diseases affecting humans and animals. Also known as the transmissible spongiform encephalopathies, for the hallmark spongiform change seen in the brain, these diseases manifest increased oxidative damage ...

Abstract	Prion diseases are progressive, neurodegenerative diseases affecting humans and animals. Also known as the transmissible spongiform encephalopathies, for the hallmark spongiform change seen in the brain, these diseases manifest increased oxidative damage early in disease and changes in antioxidant enzymes in terminal brain tissue. Superoxide dismutase 2 (SOD2) is an antioxidant enzyme that is critical for life. SOD2 knock-out mice can only be kept alive for several weeks post-birth and only with antioxidant therapy. However, this results in the development of a spongiform encephalopathy. Consequently, we hypothesized that reduced levels of SOD2 may accelerate prion disease progression and play a critical role in the formation of spongiform change. Using SOD2 heterozygous knock-out and litter mate wild-type controls, we examined neuronal long-term potentiation, disease duration, pathology, and degree of spongiform change in mice infected with three strains of mouse adapted scrapie. No influence of the reduced SOD2 expression was observed in any parameter measured for any strain. We conclude that changes relating to SOD2 during prion disease are most likely secondary to the disease processes causing toxicity and do not influence the development of spongiform pathology.
MeSH term(s)	Animals ; Blotting, Western ; Electrophysiology ; Immunohistochemistry ; Male ; Mice ; Mice, Knockout ; Mice, Mutant Strains ; Prion Diseases/genetics ; Prion Diseases/metabolism ; Superoxide Dismutase/genetics ; Superoxide Dismutase/metabolism
Chemical Substances	Superoxide Dismutase (EC 1.15.1.1) ; superoxide dismutase 2 (EC 1.15.1.1)
Language	English
Publishing date	2021-11-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0259597
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Article ; Online: Hereditary E200K mutation within the prion protein gene alters human iPSC derived cardiomyocyte function.

Wood, Aleksandar R / Foliaki, Simote T / Groveman, Bradley R / Walters, Ryan O / Williams, Katie / Yuan, Jue / Zou, Wen-Quan / Haigh, Cathryn L

Scientific reports

2022 Volume 12, Issue 1, Page(s) 15788

Abstract: Cardiomyopathy is a co-morbidity of some prion diseases including genetic disease caused by mutations within the PrP gene (PRNP). Although the cellular prion protein (PrP) has been shown to protect against cardiotoxicity caused by oxidative stress, it is ...

Abstract	Cardiomyopathy is a co-morbidity of some prion diseases including genetic disease caused by mutations within the PrP gene (PRNP). Although the cellular prion protein (PrP) has been shown to protect against cardiotoxicity caused by oxidative stress, it is unclear if the cardiomyopathy is directly linked to PrP dysfunction. We differentiated cardiomyocyte cultures from donor human induced pluripotent stem cells and found a direct influence of the PRNP E200K mutation on cellular function. The PRNP E200K cardiomyocytes showed abnormal function evident in the irregularity of the rapid repolarization; a phenotype comparable with the dysfunction reported in Down Syndrome cardiomyocytes. PRNP E200K cardiomyocyte cultures also showed increased mitochondrial superoxide accompanied by increased mitochondrial membrane potential and dysfunction. To confirm that the changes were due to the E200K mutation, CRISPR-Cas9 engineering was used to correct the E200K carrier cells and insert the E200K mutation into control cells. The isotype matched cardiomyocytes showed that the lysine expressing allele does directly influence electrophysiology and mitochondrial function but some differences in severity were apparent between donor lines. Our results demonstrate that cardiomyopathy in hereditary prion disease may be directly linked to PrP dysfunction.
MeSH term(s)	Creutzfeldt-Jakob Syndrome/genetics ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Lysine/genetics ; Mutation ; Myocytes, Cardiac/metabolism ; Prion Proteins/genetics ; Superoxides
Chemical Substances	PRNP protein, human ; Prion Proteins ; Superoxides (11062-77-4) ; Lysine (K3Z4F929H6)
Language	English
Publishing date	2022-09-22
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-19631-5
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