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Article ; Online: Spinal cord and brain concentrations of riluzole after oral and intrathecal administration: A potential new treatment route for amyotrophic lateral sclerosis.

Keifer, Orion P / Gutierrez, Juanmarco / Butt, Mark T / Cramer, Sarah D / Bartus, Raymond / Tansey, Malu / Deaver, Daniel / Betourne, Alexandre / Boulis, Nicholas M

PloS one

2023 Volume 18, Issue 8, Page(s) e0277718

Abstract: Riluzole is the only treatment known to improve survival in patients with Amyotrophic Lateral Sclerosis (ALS). However, oral riluzole efficacy is modest at best, further it is known to have large inter-individual variability of serum concentration and ... ...

Abstract	Riluzole is the only treatment known to improve survival in patients with Amyotrophic Lateral Sclerosis (ALS). However, oral riluzole efficacy is modest at best, further it is known to have large inter-individual variability of serum concentration and clearance, is formulated as an oral drug in a patient population plagued with dysphagia, and has known systemic side-effects like asthenia (limiting patient compliance) and elevated liver enzymes. In this context, we postulated that continuous intrathecal (IT) infusion of low doses of riluzole could provide consistent elevations of the drug spinal cord (SC) concentrations at or above those achieved with oral dosing, without increasing the risk for adverse events associated with systemic drug exposure or off-target side effects in the brain. We developed a formulation of riluzole for IT delivery and conducted our studies in purpose-bred hound dogs. Our non-GLP studies revealed that IT infusion alone was able to increase SC concentrations above those provided by oral administration, without increasing plasma concentrations. We then conducted two GLP studies that combined IT infusion with oral administration at human equivalent dose, to evaluate SC and brain concentrations of riluzole along with assessments of safety and tolerability. In the 6-week study, the highest IT dose (0.2 mg/hr) was well tolerated by the animals and increased SC concentrations above those achieved with oral riluzole alone, without increasing brain concentrations. In the 6-month study, the highest dose tested (0.4 mg/hr) was not tolerated and yielded SC significantly above those achieved in all previous studies. Our data show the feasibility and safety profile of continuous IT riluzole delivery to the spinal cord, without concurrent elevated liver enzymes, and minimal brain concentrations creating another potential therapeutic route of delivery to be used in isolation or in combination with other therapeutics."
MeSH term(s)	Humans ; Animals ; Dogs ; Amyotrophic Lateral Sclerosis/drug therapy ; Riluzole/therapeutic use ; Brain ; Administration, Oral ; Drug-Related Side Effects and Adverse Reactions
Chemical Substances	Riluzole (7LJ087RS6F)
Language	English
Publishing date	2023-08-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0277718
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Article ; Online: The future of rare disease drug development: the rare disease cures accelerator data analytics platform (RDCA-DAP).

Barrett, Jeffrey S / Betourne, Alexandre / Walls, Ramona L / Lasater, Kara / Russell, Scott / Borens, Amanda / Rohatagi, Shlok / Roddy, Will

Journal of pharmacokinetics and pharmacodynamics

2023 Volume 50, Issue 6, Page(s) 507–519

Abstract: Rare disease drug development is wrought with challenges not the least of which is access to the limited data currently available throughout the rare disease ecosystem where sharing of the available data is not guaranteed. Most pharmaceutical sponsors ... ...

Abstract	Rare disease drug development is wrought with challenges not the least of which is access to the limited data currently available throughout the rare disease ecosystem where sharing of the available data is not guaranteed. Most pharmaceutical sponsors seeking to develop agents to treat rare diseases will initiate data landscaping efforts to identify various data sources that might be informative with respect to disease prevalence, patient selection and identification, disease progression and any data projecting likelihood of patient response to therapy including any genetic data. Such data are often difficult to come by for highly prevalent, mainstream disease populations let alone for the 8000 rare disease that make up the pooled patient population of rare disease patients. The future of rare disease drug development will hopefully rely on increased data sharing and collaboration among the entire rare disease ecosystem. One path to achieving this outcome has been the development of the rare disease cures accelerator, data analytics platform (RDCA-DAP) funded by the US FDA and operationalized by the Critical Path Institute. FDA intentions were clearly focused on improving the quality of rare disease regulatory applications by sponsors seeking to develop treatment options for various rare disease populations. As this initiative moves into its second year of operations it is envisioned that the increased connectivity to new and diverse data streams and tools will result in solutions that benefit the entire rare disease ecosystem and that the platform becomes a Collaboratory for engagement of this ecosystem that also includes patients and caregivers.
MeSH term(s)	Humans ; Data Science ; Disease Progression ; Rare Diseases/drug therapy
Language	English
Publishing date	2023-05-02
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2041601-5
ISSN	1573-8744 ; 1567-567X
ISSN (online)	1573-8744
ISSN	1567-567X
DOI	10.1007/s10928-023-09859-7
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Zs.A 980: Show issues

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Article ; Online: Innovations in Therapy Development for Rare Diseases Through the Rare Disease Cures Accelerator-Data and Analytics Platform.

Larkindale, Jane / Betourne, Alexandre / Borens, Amanda / Boulanger, Vanessa / Theurer Crider, Vickie / Gavin, Pamela / Burton, Jackson / Liwski, Richard / Romero, Klaus / Walls, Ramona / Barrett, Jeffrey S

Therapeutic innovation & regulatory science

2022 Volume 56, Issue 5, Page(s) 768–776

Abstract: Rare diseases impact the lives of an estimated 350 million people worldwide, and yet about 90% of rare diseases remain without an approved treatment. New technologies have become available, such as gene and oligonucleotide therapies, that offer great ... ...

Abstract	Rare diseases impact the lives of an estimated 350 million people worldwide, and yet about 90% of rare diseases remain without an approved treatment. New technologies have become available, such as gene and oligonucleotide therapies, that offer great promise in treating rare diseases. However, progress toward the development of therapies to treat these diseases is hampered by a limited understanding of the course of each rare disease, how changes in disease progression occur and can be effectively measured over time, and challenges in designing and running clinical trials in diseases where the natural history is poorly characterized. Data that could be used to characterize the natural history of each disease has often been collected in various ways, including in electronic health records, patient-report registries, clinical natural history studies, and in past clinical trials. However, each data source contains a limited number of subjects and different data elements, and data is frequently kept proprietary in the hands of the study sponsor rather than shared widely across the rare disease community. The Rare Disease Cures Accelerator-Data and Analytics Platform (RDCA-DAP) is an FDA-funded effort to overcome these persistent challenges. By aggregating data across all rare diseases and making that data available to the community to support understanding of rare disease natural history and inform drug development, RDCA-DAP aims to accelerate the regulatory approval of new therapies. RDCA-DAP curates, standardizes, and tags data across rare disease datasets to make it findable within the database, and contains a built-in analytics platform to help visualize, interpret, and use it to support drug development. RDCA-DAP will coordinate data and tool resources across non-profit, commercial, and for-profit entities to serve a diverse array of rare disease stakeholders that includes academic researchers, drug developers, FDA reviewers and of course patients and their caregivers. Drug development programs utilizing the RDCA-DAP will be able to leverage existing data to support their efforts and reach definitive decisions on the efficacy of their therapeutics more efficiently and more rapidly than ever.
MeSH term(s)	Databases, Factual ; Drug Development ; Humans ; Rare Diseases/drug therapy ; Registries
Language	English
Publishing date	2022-06-06
Publishing country	Switzerland
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	2708397-4
ISSN	2168-4804 ; 2168-4790
ISSN (online)	2168-4804
ISSN	2168-4790
DOI	10.1007/s43441-022-00408-x
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Article ; Online: HSPA9/Mortalin mediates axo-protection and modulates mitochondrial dynamics in neurons.

Ferré, Cécile A / Thouard, Anne / Bétourné, Alexandre / Le Dorze, Anne-Louise / Belenguer, Pascale / Miquel, Marie-Christine / Peyrin, Jean-Michel / Gonzalez-Dunia, Daniel / Szelechowski, Marion

Scientific reports

2021 Volume 11, Issue 1, Page(s) 17705

Abstract: Mortalin is a mitochondrial chaperone protein involved in quality control of proteins imported into the mitochondrial matrix, which was recently described as a sensor of neuronal stress. Mortalin is down-regulated in neurons of patients with ... ...

Abstract	Mortalin is a mitochondrial chaperone protein involved in quality control of proteins imported into the mitochondrial matrix, which was recently described as a sensor of neuronal stress. Mortalin is down-regulated in neurons of patients with neurodegenerative diseases and levels of Mortalin expression are correlated with neuronal fate in animal models of Alzheimer's disease or cerebral ischemia. To date, however, the links between Mortalin levels, its impact on mitochondrial function and morphology and, ultimately, the initiation of neurodegeneration, are still unclear. In the present study, we used lentiviral vectors to over- or under-express Mortalin in primary neuronal cultures. We first analyzed the early events of neurodegeneration in the axonal compartment, using oriented neuronal cultures grown in microfluidic-based devices. We observed that Mortalin down-regulation induced mitochondrial fragmentation and axonal damage, whereas its over-expression conferred protection against axonal degeneration mediated by rotenone exposure. We next demonstrated that Mortalin levels modulated mitochondrial morphology by acting on DRP1 phosphorylation, thereby further illustrating the crucial implication of mitochondrial dynamics on neuronal fate in degenerative diseases.
MeSH term(s)	Animals ; Cerebral Cortex/drug effects ; Cerebral Cortex/metabolism ; HSP70 Heat-Shock Proteins/genetics ; HSP70 Heat-Shock Proteins/metabolism ; Mitochondrial Dynamics/drug effects ; Mitochondrial Dynamics/physiology ; Neurons/drug effects ; Neurons/metabolism ; Rats ; Rats, Sprague-Dawley ; Rotenone/pharmacology
Chemical Substances	HSP70 Heat-Shock Proteins ; mortalin ; Rotenone (03L9OT429T)
Language	English
Publishing date	2021-09-06
Publishing country	England
Document type	Journal Article ; 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/s41598-021-97162-1
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Article ; Online: Focal and dose-dependent neuroprotection in ALS mice following AAV2-neurturin delivery.

Gross, Sarah K / Shim, Bo Sung / Bartus, Raymond T / Deaver, Dan / McEachin, Zachary / Bétourné, Alexandre / Boulis, Nicholas M / Maragakis, Nicholas J

Experimental neurology

2019 Volume 323, Page(s) 113091

Abstract: Neurotrophic factors as candidates for ALS therapeutics have previously been studied in the context of attempts to slow disease progression. For a variety of reasons, clinical trials of neurotrophic factors have failed to show efficacy in ALS patients. ... ...

Abstract	Neurotrophic factors as candidates for ALS therapeutics have previously been studied in the context of attempts to slow disease progression. For a variety of reasons, clinical trials of neurotrophic factors have failed to show efficacy in ALS patients. Previous studies in Parkinson's Disease (PD) models have shown promise with the use of recombinant adeno-associated virus serotype-2 (rAAV2)-neurturin (NRTN) [AAV2-NRTN] providing neuroprotection and behavioral improvements in preclinical models which subsequently resulted in several clinical studies in patients with PD. Given that this neurotrophic compound has not been studied in the context of ALS, we conducted a study of AAV2-NRTN to assess the preclinical safety, tolerability, biodistribution, and efficacy of this compound in an ALS mouse model. SOD1
MeSH term(s)	Amyotrophic Lateral Sclerosis ; Animals ; Cervical Cord/metabolism ; Disease Models, Animal ; Gene Transfer Techniques ; Genetic Vectors ; Humans ; Mice ; Motor Neurons/metabolism ; Neuroprotective Agents/pharmacology ; Neurturin/administration & dosage ; Parvovirinae ; Transduction, Genetic
Chemical Substances	NRTN protein, human ; Neuroprotective Agents ; Neurturin
Language	English
Publishing date	2019-10-31
Publishing country	United States
Document type	Journal Article
ZDB-ID	207148-4
ISSN	1090-2430 ; 0014-4886
ISSN (online)	1090-2430
ISSN	0014-4886
DOI	10.1016/j.expneurol.2019.113091
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Article ; Online: 321 Development of Intrathecal Riluzole: A New Route of Administration for the Treatment of Amyotrophic Lateral Sclerosis Patients.

Gutierrez, Juanmarco / Federici, Thais / Peterson, Bethany / Bartus, Ray / Betourne, Alexandre / Boulis, Nicholas M

Neurosurgery

2016 Volume 63 Suppl 1, Page(s) 193

Abstract: Introduction: Oral administration of riluzole is the only Food and Drug Administration-approved therapy for amyotrophic lateral sclerosis (ALS). However, per os riluzole therapy has shown modest efficacy and is limited by its negative impact on liver ... ...

Abstract	Introduction: Oral administration of riluzole is the only Food and Drug Administration-approved therapy for amyotrophic lateral sclerosis (ALS). However, per os riluzole therapy has shown modest efficacy and is limited by its negative impact on liver function. We hypothesize that intrathecal (IT) administration of riluzole will significantly improve drug efficacy by increasing local concentrations at targeted spinal cord segments, while circumventing peripheral toxicity. Methods: A programmable infusion pump (SynchroMed II) connected to an IT catheter (Ascenda) was implanted into Göttingen minipigs to deliver a newly developed riluzole formulation. In group 1 (n = 2), drug levels in plasma, cerebrospinal fluid (CSF) and nervous tissue were analyzed after a single bolus infusion (1 hour; 1 and 3 mg). A control group (n = 4) received riluzole orally (single doses; 0.7 and 1.4 mg/kg). Group 2 (n = 4) received a chronic infusion of riluzole intrathecally (itRIL) following a dose-escalation scheme to delineate drug dose-range tolerability. The animals were monitored for signs of toxicity using a modified Tarlov Score. A third group (group 3, n = 4) received a continuous infusion of itRIL for 1 (n = 2) and 3 weeks (n = 2) to define the time course and levels of drug accumulation in the spinal cord. Results: Analysis of riluzole pharmacokinetics after single-dose IT infusions revealed that itRIL enabled significantly higher CSF levels of riluzole while maintaining lower plasmatic levels compared with those achieved through oral administration (plasma Cmax, oral vs IT P < .01). Furthermore, the dose-escalation analysis of continuous itRIL infusion demonstrated that the formulation could be safely administered at a dose of up to 2.4 mg daily. Histology performed on nervous tissue showed that the IT route provides a 10-fold increase of riluzole concentrations in the spinal cord compared with the control group. Conclusion: Our results indicate that riluzole can be safely administered IT to provide higher drug levels in the spinal cord tissue while maintaining lower plasmatic levels, thereby circumventing peripheral side effects associated with the oral form.
Language	English
Publishing date	2016-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	135446-2
ISSN	1524-4040 ; 0148-396X
ISSN (online)	1524-4040
ISSN	0148-396X
DOI	10.1227/01.neu.0000489810.52605.80
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Zs.A 1424: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 539: Show issues

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Article ; Online: β2-Adrenoceptor agonists as novel, safe and potentially effective therapies for Amyotrophic lateral sclerosis (ALS).

Bartus, Raymond T / Bétourné, Alexandre / Basile, Anthony / Peterson, Bethany L / Glass, Jonathan / Boulis, Nicholas M

Neurobiology of disease

2016 Volume 85, Page(s) 11–24

Abstract: Amyotrophic lateral sclerosis (ALS) is a chronic and progressive neuromuscular disease for which no cure exists and better treatment options are desperately needed. We hypothesize that currently approved β2-adrenoceptor agonists may effectively treat the ...

Abstract	Amyotrophic lateral sclerosis (ALS) is a chronic and progressive neuromuscular disease for which no cure exists and better treatment options are desperately needed. We hypothesize that currently approved β2-adrenoceptor agonists may effectively treat the symptoms and possibly slow the progression of ALS. Although β2-agonists are primarily used to treat asthma, pharmacologic data from animal models of neuromuscular diseases suggest that these agents may have pharmacologic effects of benefit in treating ALS. These include inhibiting protein degradation, stimulating protein synthesis, inducing neurotrophic factor synthesis and release, positively modulating microglial and systemic immune function, maintaining the structural and functional integrity of motor endplates, and improving energy metabolism. Moreover, stimulation of β2-adrenoceptors can activate a range of downstream signaling events in many different cell types that could account for the diverse array of effects of these agents. The evidence supporting the possible therapeutic benefits of β2-agonists is briefly reviewed, followed by a more detailed review of clinical trials testing the efficacy of β-agonists in a variety of human neuromuscular maladies. The weight of evidence of the potential benefits from treating these diseases supports the hypothesis that β2-agonists may be efficacious in ALS. Finally, ways to monitor and manage the side effects that may arise with chronic administration of β2-agonists are evaluated. In sum, effective, safe and orally-active β2-agonists may provide a novel and convenient means to reduce the symptoms of ALS and possibly delay disease progression, affording a unique opportunity to repurpose these approved drugs for treating ALS, and rapidly transforming the management of this serious, unmet medical need.
MeSH term(s)	Administration, Oral ; Adrenergic beta-2 Receptor Agonists/administration & dosage ; Adrenergic beta-2 Receptor Agonists/adverse effects ; Amyotrophic Lateral Sclerosis/drug therapy ; Amyotrophic Lateral Sclerosis/metabolism ; Animals ; Humans ; Neuroprotective Agents/administration & dosage ; Neuroprotective Agents/adverse effects
Chemical Substances	Adrenergic beta-2 Receptor Agonists ; Neuroprotective Agents
Language	English
Publishing date	2016-01
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1211786-9
ISSN	1095-953X ; 0969-9961
ISSN (online)	1095-953X
ISSN	0969-9961
DOI	10.1016/j.nbd.2015.10.006
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Zs.A 4444: Show issues

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Article ; Online: Hippocampal expression of a virus-derived protein impairs memory in mice.

Bétourné, Alexandre / Szelechowski, Marion / Thouard, Anne / Abrial, Erika / Jean, Arnaud / Zaidi, Falek / Foret, Charlotte / Bonnaud, Emilie M / Charlier, Caroline M / Suberbielle, Elsa / Malnou, Cécile E / Granon, Sylvie / Rampon, Claire / Gonzalez-Dunia, Daniel

Proceedings of the National Academy of Sciences of the United States of America

2018 Volume 115, Issue 7, Page(s) 1611–1616

Abstract: The analysis of the biology of neurotropic viruses, notably of their interference with cellular signaling, provides a useful tool to get further insight into the role of specific pathways in the control of behavioral functions. Here, we exploited the ... ...

Abstract	The analysis of the biology of neurotropic viruses, notably of their interference with cellular signaling, provides a useful tool to get further insight into the role of specific pathways in the control of behavioral functions. Here, we exploited the natural property of a viral protein identified as a major effector of behavioral disorders during infection. We used the phosphoprotein (P) of Borna disease virus, which acts as a decoy substrate for protein kinase C (PKC) when expressed in neurons and disrupts synaptic plasticity. By a lentiviral-based strategy, we directed the singled-out expression of P in the dentate gyrus of the hippocampus and we examined its impact on mouse behavior. Mice expressing the P protein displayed increased anxiety and impaired long-term memory in contextual and spatial memory tasks. Interestingly, these effects were dependent on P protein phosphorylation by PKC, as expression of a mutant form of P devoid of its PKC phosphorylation sites had no effect on these behaviors. We also revealed features of behavioral impairment induced by P protein expression but that were independent of its phosphorylation by PKC. Altogether, our findings provide insight into the behavioral correlates of viral infection, as well as into the impact of virus-mediated alterations of the PKC pathway on behavioral functions.
MeSH term(s)	Animals ; Borna Disease/metabolism ; Borna Disease/pathology ; Borna Disease/virology ; Borna disease virus/physiology ; Cells, Cultured ; Cognition Disorders/etiology ; Cognition Disorders/metabolism ; Cognition Disorders/pathology ; Dentate Gyrus/metabolism ; Dentate Gyrus/pathology ; Dentate Gyrus/virology ; Hippocampus/metabolism ; Hippocampus/pathology ; Hippocampus/virology ; Memory, Long-Term/physiology ; Mice ; Mutation ; Neuronal Plasticity ; Neurons/metabolism ; Neurons/pathology ; Neurons/virology ; Phosphoproteins/genetics ; Phosphoproteins/metabolism ; Phosphorylation ; Protein Kinase C/genetics ; Protein Kinase C/metabolism ; Viral Structural Proteins/genetics ; Viral Structural Proteins/metabolism
Chemical Substances	P protein, Borna disease virus ; Phosphoproteins ; Viral Structural Proteins ; Protein Kinase C (EC 2.7.11.13)
Language	English
Publishing date	2018--13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1711977115
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Zs.A 1148: Show issues

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Article ; Online: Borna disease virus phosphoprotein modulates epigenetic signaling in neurons to control viral replication.

Bonnaud, Emilie M / Szelechowski, Marion / Bétourné, Alexandre / Foret, Charlotte / Thouard, Anne / Gonzalez-Dunia, Daniel / Malnou, Cécile E

Journal of virology

2015 Volume 89, Issue 11, Page(s) 5996–6008

Abstract: Unlabelled: Understanding the modalities of interaction of neurotropic viruses with their target cells represents a major challenge that may improve our knowledge of many human neurological disorders for which viral origin is suspected. Borna disease ... ...

Abstract	Unlabelled: Understanding the modalities of interaction of neurotropic viruses with their target cells represents a major challenge that may improve our knowledge of many human neurological disorders for which viral origin is suspected. Borna disease virus (BDV) represents an ideal model to analyze the molecular mechanisms of viral persistence in neurons and its consequences for neuronal homeostasis. It is now established that BDV ensures its long-term maintenance in infected cells through a stable interaction of viral components with the host cell chromatin, in particular, with core histones. This has led to our hypothesis that such an interaction may trigger epigenetic changes in the host cell. Here, we focused on histone acetylation, which plays key roles in epigenetic regulation of gene expression, notably for neurons. We performed a comparative analysis of histone acetylation patterns of neurons infected or not infected by BDV, which revealed that infection decreases histone acetylation on selected lysine residues. We showed that the BDV phosphoprotein (P) is responsible for these perturbations, even when it is expressed alone independently of the viral context, and that this action depends on its phosphorylation by protein kinase C. We also demonstrated that BDV P inhibits cellular histone acetyltransferase activities. Finally, by pharmacologically manipulating cellular acetylation levels, we observed that inhibiting cellular acetyl transferases reduces viral replication in cell culture. Our findings reveal that manipulation of cellular epigenetics by BDV could be a means to modulate viral replication and thus illustrate a fascinating example of virus-host cell interaction. Importance: Persistent DNA viruses often subvert the mechanisms that regulate cellular chromatin dynamics, thereby benefitting from the resulting epigenetic changes to create a favorable milieu for their latent and persistent states. Here, we reasoned that Borna disease virus (BDV), the only RNA virus known to durably persist in the nucleus of infected cells, notably neurons, might employ a similar mechanism. In this study, we uncovered a novel modality of virus-cell interaction in which BDV phosphoprotein inhibits cellular histone acetylation by interfering with histone acetyltransferase activities. Manipulation of cellular histone acetylation is accompanied by a modulation of viral replication, revealing a perfect adaptation of this "ancient" virus to its host that may favor neuronal persistence and limit cellular damage.
MeSH term(s)	Acetylation ; Animals ; Borna disease virus/physiology ; Cells, Cultured ; Epigenesis, Genetic ; Histones/metabolism ; Host-Pathogen Interactions ; Neurons/virology ; Phosphoproteins/metabolism ; Protein Processing, Post-Translational ; Rats, Sprague-Dawley ; Viral Structural Proteins/metabolism ; Virus Replication
Chemical Substances	Histones ; P protein, Borna disease virus ; Phosphoproteins ; Viral Structural Proteins
Language	English
Publishing date	2015-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.00454-15
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Article ; Online: A viral peptide that targets mitochondria protects against neuronal degeneration in models of Parkinson's disease.

Szelechowski, Marion / Bétourné, Alexandre / Monnet, Yann / Ferré, Cécile A / Thouard, Anne / Foret, Charlotte / Peyrin, Jean-Michel / Hunot, Stéphane / Gonzalez-Dunia, Daniel

Nature communications

2014 Volume 5, Page(s) 5181

Abstract: Mitochondrial dysfunction is a common feature of many neurodegenerative disorders, notably Parkinson's disease. Consequently, agents that protect mitochondria have strong therapeutic potential. Here, we sought to divert the natural strategy used by Borna ...

Abstract	Mitochondrial dysfunction is a common feature of many neurodegenerative disorders, notably Parkinson's disease. Consequently, agents that protect mitochondria have strong therapeutic potential. Here, we sought to divert the natural strategy used by Borna disease virus (BDV) to replicate in neurons without causing cell death. We show that the BDV X protein has strong axoprotective properties, thereby protecting neurons from degeneration both in tissue culture and in an animal model of Parkinson's disease, even when expressed alone outside of the viral context. We also show that intranasal administration of a cell-permeable peptide derived from the X protein is neuroprotective. We establish that both the X protein and the X-derived peptide act by buffering mitochondrial damage and inducing enhanced mitochondrial filamentation. Our results open the way to novel therapies for neurodegenerative diseases by targeting mitochondrial dynamics and thus preventing the earliest steps of neurodegenerative processes in axons.
MeSH term(s)	Animals ; Axons/metabolism ; Axons/physiology ; Disease Models, Animal ; Female ; HEK293 Cells ; Humans ; Male ; Membrane Potential, Mitochondrial ; Mice ; Mice, Inbred C57BL ; Microfluidics ; Microscopy, Confocal ; Microscopy, Fluorescence ; Mitochondria/pathology ; Neurodegenerative Diseases/prevention & control ; Neurodegenerative Diseases/virology ; Neurons/metabolism ; Parkinson Disease/prevention & control ; Parkinson Disease/virology ; Peptides/chemistry ; Phosphorylation ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Rotenone/chemistry ; Viral Nonstructural Proteins/chemistry
Chemical Substances	Peptides ; Reactive Oxygen Species ; Viral Nonstructural Proteins ; Rotenone (03L9OT429T)
Language	English
Publishing date	2014-10-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2041-1723
ISSN (online)	2041-1723
DOI	10.1038/ncomms6181
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