Persistent, non‐cytolytic infection of neurons by Borna disease virus interferes with ERK 1/2 signaling and abrogates BDNF‐induced synaptogenesis

Hans, Aymeric; Bajramović, Jeffrey J.; Syan, Sylvie; Perret, Emmanuelle; Dunia, I.; Brahic, Michel; Gonzalez–Dunia, Daniel

doi:10.1096/fj.03-0764fje

Cited by 69 publications

(80 citation statements)

References 49 publications

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“…The virus enters the cells, replicates, and propagates very efficiently. The rapidity of propagation is comparable to that observed in primary cultures of neurons from newborn rats (16) and is much greater than propagation in Vero cells (our unpublished observation), which are commonly used for virus titration or purification. However, although HNPCs are highly permissive to the virus, they did not appear to be particularly vulnerable.…”

Section: Discussionsupporting

confidence: 61%

“…However, although HNPCs are highly permissive to the virus, they did not appear to be particularly vulnerable. As has been observed in other cell types, including primary cultures of neurons and astrocytes from rats (16,44) and other cell lines, BDV infection proceeds without an overt pathogenic effect in HNPCs, impairing neither their survival nor their undifferentiated phenotype. Therefore, our results argue against a specific vulnerability of immature neural cells to BDV infection.…”

Section: Discussionmentioning

confidence: 56%

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Borna Disease Virus Infects Human Neural Progenitor Cells and Impairs Neurogenesis

Brnić

Stevanović

Cochet

et al. 2012

J Virol

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Understanding the complex mechanisms by which infectious agents can disrupt behavior represents a major challenge. The Borna disease virus (BDV), a potential human pathogen, provides a unique model to study such mechanisms. Because BDV induces neurodegeneration in brain areas that are still undergoing maturation at the time of infection, we tested the hypothesis that BDV interferes with neurogenesis. We showed that human neural stem/progenitor cells are highly permissive to BDV, although infection does not alter their survival or undifferentiated phenotype. In contrast, upon the induction of differentiation, BDV is capable of severely impairing neurogenesis by interfering with the survival of newly generated neurons. Such impairment was specific to neurogenesis, since astrogliogenesis was unaltered. In conclusion, we demonstrate a new mechanism by which BDV might impair neural function and brain plasticity in infected individuals. These results may contribute to a better understanding of behavioral disorders associated with BDV infection.

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 56%

Borna Disease Virus Infects Human Neural Progenitor Cells and Impairs Neurogenesis

Brnić

Stevanović

Cochet

et al. 2012

J Virol

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“…HEK-293T cells (ATCC CRL-3216) were passaged 1:10 twice a week in DMEM (Gibco) supplemented with 10% fetal calf serum (Gibco), 2 mM L-glutamine (GE Healthcare) and 0.2 mg ml À 1 geneticin (Gibco). Cellreleased virus stocks were prepared as described 57,58 using Vero cells (ATCC CCL-81) infected with either BDV (Giessen strain He/80) or recombinant viruses expressing wt or mutated X (rBDV-LRD-Xwt and rBDV-LRD-X A6A7 , a kind gift from U. Schneider, Freiburg University, Germany). Timed pregnant SpragueDawley female rats were purchased from Janvier Labs.…”

Section: Methodsmentioning

confidence: 99%

A viral peptide that targets mitochondria protects against neuronal degeneration in models of Parkinson’s disease

et al. 2014

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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 cellpermeable 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.

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“…Evidence exists that this signalling cascade mediates the synaptogenic action of neurotrophic factors (Huang and Reichardt, 2001;Alonso et al, 2004;Hans et al, 2004), although its molecular targets during synaptogenesis are still unknown. Moreover, it has been proposed that the MAPK/Erk pathway participates in long-term synaptic plasticity by regulating the activity of transcriptional factors upon nuclear translocation .…”

Section: Introductionmentioning

confidence: 99%

MAPK/Erk-dependent phosphorylation of synapsin mediates formation of functional synapses and short-term homosynaptic plasticity

Giachello

Fiumara

Giacomini³

et al. 2010

Journal of Cell Science

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SummaryMAPK/Erk is a protein kinase activated by neurotrophic factors involved in synapse formation and plasticity, which acts at both the nuclear and cytoplasmic level. Synapsin proteins are synaptic-vesicle-associated proteins that are well known to be MAPK/Erk substrates at phylogenetically conserved sites. However, the physiological role of MAPK/Erk-dependent synapsin phosphorylation in regulating synaptic formation and function is poorly understood. Here, we examined whether synapsin acts as a physiological effector of MAPK/Erk in synaptogenesis and plasticity. To this aim, we developed an in vitro model of soma-to-soma paired Helix B2 neurons, that establish bidirectional excitatory synapses. We found that the formation and activity-dependent short-term plasticity of these synapses is dependent on the MAPK/Erk pathway. To address the role of synapsin in this pathway, we generated non-phosphorylatable and pseudo-phosphorylated Helix synapsin mutants at the MAPK/Erk sites. Overexpression experiments revealed that both mutants interfere with presynaptic differentiation, synapsin clustering, and severely impair post-tetanic potentiation, a form of short-term homosynaptic plasticity. Our findings show that MAPK/Erk-dependent synapsin phosphorylation has a dual role both in the establishment of functional synaptic connections and their short-term plasticity, indicating that some of the multiple extranuclear functions of MAPK/Erk in neurons can be mediated by the same multifunctional presynaptic target.

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Persistent, non‐cytolytic infection of neurons by Borna disease virus interferes with ERK 1/2 signaling and abrogates BDNF‐induced synaptogenesis

Cited by 69 publications

References 49 publications

Borna Disease Virus Infects Human Neural Progenitor Cells and Impairs Neurogenesis

Borna Disease Virus Infects Human Neural Progenitor Cells and Impairs Neurogenesis

A viral peptide that targets mitochondria protects against neuronal degeneration in models of Parkinson’s disease

MAPK/Erk-dependent phosphorylation of synapsin mediates formation of functional synapses and short-term homosynaptic plasticity

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