The Experts below are selected from a list of 216 Experts worldwide ranked by ideXlab platform
Miguel Lafarga - One of the best experts on this subject based on the ideXlab platform.
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proteasome inhibition induces dna damage and reorganizes nuclear architecture and protein synthesis machinery in Sensory Ganglion neurons
Cellular and Molecular Life Sciences, 2014Co-Authors: Ana Palanca, Iñigo Casafont, Maria T. Berciano, Miguel LafargaAbstract:Bortezomib is a reversible proteasome inhibitor used as an anticancer drug. However, its clinical use is limited since it causes peripheral neurotoxicity. We have used Sprague–Dawley rats as an animal model to investigate the cellular mechanisms affected by both short-term and chronic bortezomib treatments in Sensory ganglia neurons. Proteasome inhibition induces dose-dependent alterations in the architecture, positioning, shape and polarity of the neuronal nucleus. It also produces DNA damage without affecting neuronal survival, and severe disruption of the protein synthesis machinery at the central cytoplasm accompanied by decreased expression of the brain-derived neurotrophic factor. As a compensatory or adaptive survival response against proteotoxic stress caused by bortezomib treatment, Sensory neurons preserve basal levels of transcriptional activity, up-regulate the expression of proteasome subunit genes, and generate a new cytoplasmic perinuclear domain for protein synthesis. We propose that proteasome activity is crucial for controlling nuclear architecture, DNA repair and the organization of the protein synthesis machinery in Sensory neurons. These neurons are primary targets of bortezomib neurotoxicity, for which reason their dysfunction may contribute to the pathogenesis of the bortezomib-induced peripheral neuropathy in treated patients.
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Reactive nucleolar and Cajal body responses to proteasome inhibition in Sensory Ganglion neurons.
Biochimica et biophysica acta, 2013Co-Authors: Ana Palanca, Iñigo Casafont, Maria T. Berciano, Miguel LafargaAbstract:Abstract The dysfunction of the ubiquitin proteasome system has been related to a broad array of neurodegenerative disorders in which the accumulation of misfolded protein aggregates causes proteotoxicity. The ability of proteasome inhibitors to induce cell cycle arrest and apoptosis has emerged as a powerful strategy for cancer therapy. Bortezomib is a proteasome inhibitor used as an antineoplastic drug, although its neurotoxicity frequently causes a severe Sensory peripheral neuropathy. In this study we used a rat model of bortezomib treatment to study the nucleolar and Cajal body responses to the proteasome inhibition in Sensory Ganglion neurons that are major targets of bortezomib-induced neurotoxicity. Treatment with bortezomib induced dose-dependent dissociation of protein synthesis machinery (chromatolysis) and nuclear retention of poly(A) RNA granules resulting in neuronal dysfunction. However, as a compensatory response to the proteotoxic stress, both nucleoli and Cajal bodies exhibited reactive changes. These include an increase in the number and size of nucleoli, strong nucleolar incorporation of the RNA precursor 5′-fluorouridine, and increased expression of both 45S rRNA and genes encoding nucleolar proteins UBF, fibrillarin and B23. Taken together, these findings appear to reflect the activation of the nucleolar transcription in response to proteotoxic stress Furthermore, the number of Cajal bodies, a parameter related to transcriptional activity, increases upon proteasome inhibition. We propose that nucleoli and Cajal bodies are important targets in the signaling pathways that are activated by the proteotoxic stress response to proteasome inhibition. The coordinating activity of these two organelles in the production of snRNA, snoRNA and rRNA may contribute to neuronal survival after proteasome inhibition. This article is part of a Special Issue entitled: Role of the Nucleolus in Human Disease.
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Effect of ionizing radiation in Sensory Ganglion neurons: organization and dynamics of nuclear compartments of DNA damage/repair and their relationship with transcription and cell cycle.
Acta neuropathologica, 2011Co-Authors: Iñigo Casafont, Ana Palanca, Maria T. Berciano, Vanesa Lafarga, Miguel LafargaAbstract:Neurons are very sensitive to DNA damage induced by endogenous and exogenous genotoxic agents, as defective DNA repair can lead to neurodevelopmental disorders, brain tumors and neurodegenerative diseases with severe clinical manifestations. Understanding the impact of DNA damage/repair mechanisms on the nuclear organization, particularly on the regulation of transcription and cell cycle, is essential to know the pathophysiology of defective DNA repair syndromes. In this work, we study the nuclear architecture and spatiotemporal organization of chromatin compartments involved in the DNA damage response (DDR) in rat Sensory Ganglion neurons exposed to X-ray irradiation (IR). We demonstrate that the neuronal DDR involves the formation of two categories of DNA-damage processing chromatin compartments: transient, disappearing within the 1 day post-IR, and persistent, where unrepaired DNA is accumulated. Both compartments concentrate components of the DDR pathway, including γH2AX, pATM and 53BP1. Furthermore, DNA damage does not induce neuronal apoptosis but triggers the G0–G1 cell cycle phase transition, which is mediated by the activation of the ATM-p53 pathway and increased protein levels of p21 and cyclin D1. Moreover, the run on transcription assay reveals a severe inhibition of transcription at 0.5 h post-IR, followed by its rapid recovery over the 1 day post-IR in parallel with the progression of DNA repair. Therefore, the response of healthy neurons to DNA damage involves a transcription- and cell cycle-dependent but apoptosis-independent process. Furthermore, we propose that the segregation of unrepaired DNA in a few persistent chromatin compartments preserves genomic stability of undamaged DNA and the global transcription rate in neurons.
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effect of ionizing radiation in Sensory Ganglion neurons organization and dynamics of nuclear compartments of dna damage repair and their relationship with transcription and cell cycle
Acta Neuropathologica, 2011Co-Authors: Iñigo Casafont, Ana Palanca, Maria T. Berciano, Vanesa Lafarga, Miguel LafargaAbstract:Neurons are very sensitive to DNA damage induced by endogenous and exogenous genotoxic agents, as defective DNA repair can lead to neurodevelopmental disorders, brain tumors and neurodegenerative diseases with severe clinical manifestations. Understanding the impact of DNA damage/repair mechanisms on the nuclear organization, particularly on the regulation of transcription and cell cycle, is essential to know the pathophysiology of defective DNA repair syndromes. In this work, we study the nuclear architecture and spatiotemporal organization of chromatin compartments involved in the DNA damage response (DDR) in rat Sensory Ganglion neurons exposed to X-ray irradiation (IR). We demonstrate that the neuronal DDR involves the formation of two categories of DNA-damage processing chromatin compartments: transient, disappearing within the 1 day post-IR, and persistent, where unrepaired DNA is accumulated. Both compartments concentrate components of the DDR pathway, including γH2AX, pATM and 53BP1. Furthermore, DNA damage does not induce neuronal apoptosis but triggers the G0–G1 cell cycle phase transition, which is mediated by the activation of the ATM-p53 pathway and increased protein levels of p21 and cyclin D1. Moreover, the run on transcription assay reveals a severe inhibition of transcription at 0.5 h post-IR, followed by its rapid recovery over the 1 day post-IR in parallel with the progression of DNA repair. Therefore, the response of healthy neurons to DNA damage involves a transcription- and cell cycle-dependent but apoptosis-independent process. Furthermore, we propose that the segregation of unrepaired DNA in a few persistent chromatin compartments preserves genomic stability of undamaged DNA and the global transcription rate in neurons.
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pml bodies in reactive Sensory Ganglion neurons of the guillain barre syndrome
Neurobiology of Disease, 2004Co-Authors: Nuria T. Villagra, Iñigo Casafont, Miguel Lafarga, José Berciano, Marcos Altable, Joaquín Navascués, Maria T. BercianoAbstract:Abstract Acute inflammatory demyelinating polyneuropathy (AIDP) is a type of Guillain–Barre syndrome (GBS) characterized by primary nerve demyelination sometimes with secondary axonal degeneration. Studies on the fine structure of dorsal root ganglia in AIDP are lacking. Our aim was to investigate the cytology and nuclear organization of primary Sensory neurons in AIDP with axonal injury using ultrastructural and immunohistochemical analysis. The light cytology of the L5 dorsal Ganglion showed the characteristic findings of neuronal axonal reaction. The organization of chromatin, nucleolus, Cajal bodies, and nuclear pores corresponded to transcriptionally active neurons. However, the hallmark of the nuclear response to axonal injury was the formation of numerous nuclear bodies (NBs; 6.37 ± 0.6, in the AIDP, vs. 2.53 ± 0.2, in the control, mean ± SDM), identified as promyelocytic leukemia (PML) bodies by the presence of the protein PML. In addition to PML protein, nuclear bodies contained SUMO-1 and the transcriptional regulators CREB-binding protein (CBP) and glucocorticoid receptor (GR). The presence of proteasome 19S was also detected in some nuclear bodies. We suggest that neuronal PML bodies could regulate the nuclear concentration of active proteins, a process mediated by protein interactions with PML and SUMO-1 proteins. In the AIDP case, the proliferation of PML bodies may result from the overexpression of some nuclear proteins due to changes in gene expression associated with axonal injury.
Maria T. Berciano - One of the best experts on this subject based on the ideXlab platform.
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proteasome inhibition induces dna damage and reorganizes nuclear architecture and protein synthesis machinery in Sensory Ganglion neurons
Cellular and Molecular Life Sciences, 2014Co-Authors: Ana Palanca, Iñigo Casafont, Maria T. Berciano, Miguel LafargaAbstract:Bortezomib is a reversible proteasome inhibitor used as an anticancer drug. However, its clinical use is limited since it causes peripheral neurotoxicity. We have used Sprague–Dawley rats as an animal model to investigate the cellular mechanisms affected by both short-term and chronic bortezomib treatments in Sensory ganglia neurons. Proteasome inhibition induces dose-dependent alterations in the architecture, positioning, shape and polarity of the neuronal nucleus. It also produces DNA damage without affecting neuronal survival, and severe disruption of the protein synthesis machinery at the central cytoplasm accompanied by decreased expression of the brain-derived neurotrophic factor. As a compensatory or adaptive survival response against proteotoxic stress caused by bortezomib treatment, Sensory neurons preserve basal levels of transcriptional activity, up-regulate the expression of proteasome subunit genes, and generate a new cytoplasmic perinuclear domain for protein synthesis. We propose that proteasome activity is crucial for controlling nuclear architecture, DNA repair and the organization of the protein synthesis machinery in Sensory neurons. These neurons are primary targets of bortezomib neurotoxicity, for which reason their dysfunction may contribute to the pathogenesis of the bortezomib-induced peripheral neuropathy in treated patients.
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Reactive nucleolar and Cajal body responses to proteasome inhibition in Sensory Ganglion neurons.
Biochimica et biophysica acta, 2013Co-Authors: Ana Palanca, Iñigo Casafont, Maria T. Berciano, Miguel LafargaAbstract:Abstract The dysfunction of the ubiquitin proteasome system has been related to a broad array of neurodegenerative disorders in which the accumulation of misfolded protein aggregates causes proteotoxicity. The ability of proteasome inhibitors to induce cell cycle arrest and apoptosis has emerged as a powerful strategy for cancer therapy. Bortezomib is a proteasome inhibitor used as an antineoplastic drug, although its neurotoxicity frequently causes a severe Sensory peripheral neuropathy. In this study we used a rat model of bortezomib treatment to study the nucleolar and Cajal body responses to the proteasome inhibition in Sensory Ganglion neurons that are major targets of bortezomib-induced neurotoxicity. Treatment with bortezomib induced dose-dependent dissociation of protein synthesis machinery (chromatolysis) and nuclear retention of poly(A) RNA granules resulting in neuronal dysfunction. However, as a compensatory response to the proteotoxic stress, both nucleoli and Cajal bodies exhibited reactive changes. These include an increase in the number and size of nucleoli, strong nucleolar incorporation of the RNA precursor 5′-fluorouridine, and increased expression of both 45S rRNA and genes encoding nucleolar proteins UBF, fibrillarin and B23. Taken together, these findings appear to reflect the activation of the nucleolar transcription in response to proteotoxic stress Furthermore, the number of Cajal bodies, a parameter related to transcriptional activity, increases upon proteasome inhibition. We propose that nucleoli and Cajal bodies are important targets in the signaling pathways that are activated by the proteotoxic stress response to proteasome inhibition. The coordinating activity of these two organelles in the production of snRNA, snoRNA and rRNA may contribute to neuronal survival after proteasome inhibition. This article is part of a Special Issue entitled: Role of the Nucleolus in Human Disease.
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Effect of ionizing radiation in Sensory Ganglion neurons: organization and dynamics of nuclear compartments of DNA damage/repair and their relationship with transcription and cell cycle.
Acta neuropathologica, 2011Co-Authors: Iñigo Casafont, Ana Palanca, Maria T. Berciano, Vanesa Lafarga, Miguel LafargaAbstract:Neurons are very sensitive to DNA damage induced by endogenous and exogenous genotoxic agents, as defective DNA repair can lead to neurodevelopmental disorders, brain tumors and neurodegenerative diseases with severe clinical manifestations. Understanding the impact of DNA damage/repair mechanisms on the nuclear organization, particularly on the regulation of transcription and cell cycle, is essential to know the pathophysiology of defective DNA repair syndromes. In this work, we study the nuclear architecture and spatiotemporal organization of chromatin compartments involved in the DNA damage response (DDR) in rat Sensory Ganglion neurons exposed to X-ray irradiation (IR). We demonstrate that the neuronal DDR involves the formation of two categories of DNA-damage processing chromatin compartments: transient, disappearing within the 1 day post-IR, and persistent, where unrepaired DNA is accumulated. Both compartments concentrate components of the DDR pathway, including γH2AX, pATM and 53BP1. Furthermore, DNA damage does not induce neuronal apoptosis but triggers the G0–G1 cell cycle phase transition, which is mediated by the activation of the ATM-p53 pathway and increased protein levels of p21 and cyclin D1. Moreover, the run on transcription assay reveals a severe inhibition of transcription at 0.5 h post-IR, followed by its rapid recovery over the 1 day post-IR in parallel with the progression of DNA repair. Therefore, the response of healthy neurons to DNA damage involves a transcription- and cell cycle-dependent but apoptosis-independent process. Furthermore, we propose that the segregation of unrepaired DNA in a few persistent chromatin compartments preserves genomic stability of undamaged DNA and the global transcription rate in neurons.
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effect of ionizing radiation in Sensory Ganglion neurons organization and dynamics of nuclear compartments of dna damage repair and their relationship with transcription and cell cycle
Acta Neuropathologica, 2011Co-Authors: Iñigo Casafont, Ana Palanca, Maria T. Berciano, Vanesa Lafarga, Miguel LafargaAbstract:Neurons are very sensitive to DNA damage induced by endogenous and exogenous genotoxic agents, as defective DNA repair can lead to neurodevelopmental disorders, brain tumors and neurodegenerative diseases with severe clinical manifestations. Understanding the impact of DNA damage/repair mechanisms on the nuclear organization, particularly on the regulation of transcription and cell cycle, is essential to know the pathophysiology of defective DNA repair syndromes. In this work, we study the nuclear architecture and spatiotemporal organization of chromatin compartments involved in the DNA damage response (DDR) in rat Sensory Ganglion neurons exposed to X-ray irradiation (IR). We demonstrate that the neuronal DDR involves the formation of two categories of DNA-damage processing chromatin compartments: transient, disappearing within the 1 day post-IR, and persistent, where unrepaired DNA is accumulated. Both compartments concentrate components of the DDR pathway, including γH2AX, pATM and 53BP1. Furthermore, DNA damage does not induce neuronal apoptosis but triggers the G0–G1 cell cycle phase transition, which is mediated by the activation of the ATM-p53 pathway and increased protein levels of p21 and cyclin D1. Moreover, the run on transcription assay reveals a severe inhibition of transcription at 0.5 h post-IR, followed by its rapid recovery over the 1 day post-IR in parallel with the progression of DNA repair. Therefore, the response of healthy neurons to DNA damage involves a transcription- and cell cycle-dependent but apoptosis-independent process. Furthermore, we propose that the segregation of unrepaired DNA in a few persistent chromatin compartments preserves genomic stability of undamaged DNA and the global transcription rate in neurons.
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pml bodies in reactive Sensory Ganglion neurons of the guillain barre syndrome
Neurobiology of Disease, 2004Co-Authors: Nuria T. Villagra, Iñigo Casafont, Miguel Lafarga, José Berciano, Marcos Altable, Joaquín Navascués, Maria T. BercianoAbstract:Abstract Acute inflammatory demyelinating polyneuropathy (AIDP) is a type of Guillain–Barre syndrome (GBS) characterized by primary nerve demyelination sometimes with secondary axonal degeneration. Studies on the fine structure of dorsal root ganglia in AIDP are lacking. Our aim was to investigate the cytology and nuclear organization of primary Sensory neurons in AIDP with axonal injury using ultrastructural and immunohistochemical analysis. The light cytology of the L5 dorsal Ganglion showed the characteristic findings of neuronal axonal reaction. The organization of chromatin, nucleolus, Cajal bodies, and nuclear pores corresponded to transcriptionally active neurons. However, the hallmark of the nuclear response to axonal injury was the formation of numerous nuclear bodies (NBs; 6.37 ± 0.6, in the AIDP, vs. 2.53 ± 0.2, in the control, mean ± SDM), identified as promyelocytic leukemia (PML) bodies by the presence of the protein PML. In addition to PML protein, nuclear bodies contained SUMO-1 and the transcriptional regulators CREB-binding protein (CBP) and glucocorticoid receptor (GR). The presence of proteasome 19S was also detected in some nuclear bodies. We suggest that neuronal PML bodies could regulate the nuclear concentration of active proteins, a process mediated by protein interactions with PML and SUMO-1 proteins. In the AIDP case, the proliferation of PML bodies may result from the overexpression of some nuclear proteins due to changes in gene expression associated with axonal injury.
Richard B. Tenser - One of the best experts on this subject based on the ideXlab platform.
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Herpes zoster and the prevention of postherpetic neuralgia: beyond antiviral therapy.
Neurology, 2005Co-Authors: Richard B. Tenser, Robert H. DworkinAbstract:Latent infection and reactivation are common after infection by herpesviruses. For the neurotrophic human herpesviruses, herpes simplex virus type 1 (HSV-1), HSV-2, and varicella-zoster virus (VZV), the site of latency and reactivation usually is Sensory Ganglion neurons. Pain of varying intensity is a common clinical concomitant of HSV and VZV reactivation. Clinically apparent VZV reactivation, termed herpes zoster (shingles), may cause pain that continues months or years after the cutaneous infection has cleared. This postherpetic neuralgia (PHN) is the most common complication of VZV reactivation in immunocompetent patients and it can be a source of considerable physical and psychosocial morbidity.1 During HSV latency a single viral-encoded RNA is expressed in latently infected Sensory Ganglion neurons and also in autonomic neurons. This latency-associated transcript is expressed only in neurons,2 and viral protein is probably not expressed. During VZV latency, one or more viral-encoded RNAs are expressed in Sensory Ganglion neurons, and viral protein can be detected.3 Furthermore, while these molecular markers of VZV latency are expressed in Ganglion neurons, they may also be present in Ganglion satellite cells.2 Clinically, multiple occurrences of HSV reactivation, in a dermatome or part of a dermatome (e.g., the left lower lip), are common. However, multiple occurrences of zoster in a given dermatome are uncommon. The differing clinical patterns of HSV and VZV reactivation are probably related to differing molecular aspects of latency and the neurobiology of the respective infections. HSV …
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Reversible decrease of fluoride resistant acid phosphatase-positive neurons after herpes simplex virus infection.
Neuroscience letters, 1991Co-Authors: Richard B. Tenser, Anne L. Viselh, David H. SavageAbstract:Herpes simplex virus (HSV) frequently infects human Sensory Ganglion neurons, and similar infections have been reported in experimental animals. Reported here is an investigation of in vivo neuronal function after HSV infection. It was observed that the proportion of fluoride resistant acid phosphatase (FRAP)-positive trigeminal Ganglion neurons was decreased for several months after experimental infection of mice, and it is suggested that other neuronal functions may also be altered by HSV.
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Role of Herpes simplex Virus Thymidine Kinase Expression in Viral Pathogenesis and Latency
Intervirology, 1991Co-Authors: Richard B. TenserAbstract:Herpes simplex virus (HSV) thymidine kinase (TK) expression and the HSV TK gene have been evaluated in studies of gene control, as well as in animal and human studies of viral pathogenesis, including HSV latency. In investigations of the biological role of HSV TK, enzyme expression was noted to be important for HSV infection of nonreplicating cells in culture; and, in experimental animal studies, HSV TK was shown to be important for in vivo latent infection of Sensory Ganglion neurons. Latency in these studies was determined by the ability of HSV to reactivate from Sensory Ganglion explants. In recent studies, investigators sought to determine whether the role HSV TK expression plays in latency is primarily in the establishment and maintenance of latency or in the reactivation process. Following infection of experimental animals with HSV TK-deficient mutants, the presence of HSV in ganglia was detected in complementation, rescue, and molecular biological studies. Results suggest that HSV TK expression may be important for HSV reactivation from latency. This was supported by in situ hybridization investigations. In the latter studies, HSV latency associated transcript (LAT) was present in Ganglion neurons, although reactivation of HSV from such ganglia was defective. LAT-expressing, reactivation-defective infections established by TK mutants of HSV are considered examples of incomplete latency. From the present review, it appears that HSV TK expression, particularly TK expression of HSV-1, is important for the reactivation of latent HSV infection of Sensory Ganglion neurons, probably because of limited neuronal TK expression and absent replication capacity of these cells.
Péter Sántha - One of the best experts on this subject based on the ideXlab platform.
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The Insulin Receptor Is Colocalized With the TRPV1 Nociceptive Ion Channel and Neuropeptides in Pancreatic Spinal and Vagal Primary Sensory Neurons.
Pancreas, 2018Co-Authors: Bence András Lázár, Gábor Jancsó, Orsolya Oszlács, István Nagy, Péter SánthaAbstract:ObjectivesRecent observations demonstrated the expression of the insulin receptor (InsR) and its functional interaction with the transient receptor potential vanilloid type 1 receptor (TRPV1) in Sensory Ganglion neurons. Because Sensory nerves are implicated in pancreatic inflammatory processes, we
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Role of capsaicin-sensitive afferent nerves in initiation and maintenance of pathological pain
Behavioral and Brain Sciences, 1997Co-Authors: Gábor Jancsó, Mária Dux, Péter SánthaAbstract:This commentary provides experimental data in support of the critical role of capsaicin-sensitive primary afferent fibers in the initiation and maintenance of pathological pain. The demonstration of capsaicin-induced, centrally-evoked cutaneous hyperalgesia, and of neuroplastic changes elicited by the degeneration of C-fiber primary afferent terminals following peripheral nerve damage, indicates a significant contribution of capsaicin-sensitive Sensory Ganglion neurons in the development of pathological pain conditions. [coderre & katz]
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Axotomy prevents capsaicin-induced Sensory Ganglion cell degeneration
Primary Sensory Neuron, 1997Co-Authors: Péter Sántha, Ferenc Domoki, Anna Juhász, Mária Dux, Gábor JancsóAbstract:A particular group of mammalian primary afferent neurons involved in nociception is characterized by its specific sensitivity to capsaicin, the pungent principle of red pepper. A striking manifestation of neuronal capsaicin sensitivity is the degeneration of a morphologically well characterized population of Sensory Ganglion cells following a systemic injection of this compound. The present study demonstrated that prior transection of the peripheral axons of these neurons protects them from the neurotoxic action of systemically administered capsaicin. It is suggested that this phenomenon is related to an impairment of axon transport mechanisms. It is concluded that maintenance of capsaicin sensitivity is critically dependent on the integrity of the peripheral branch of the primary Sensory neuron and peripherally derived trophic factor(s) may profoundly influence the functional traits of Sensory Ganglion cells.
Iñigo Casafont - One of the best experts on this subject based on the ideXlab platform.
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proteasome inhibition induces dna damage and reorganizes nuclear architecture and protein synthesis machinery in Sensory Ganglion neurons
Cellular and Molecular Life Sciences, 2014Co-Authors: Ana Palanca, Iñigo Casafont, Maria T. Berciano, Miguel LafargaAbstract:Bortezomib is a reversible proteasome inhibitor used as an anticancer drug. However, its clinical use is limited since it causes peripheral neurotoxicity. We have used Sprague–Dawley rats as an animal model to investigate the cellular mechanisms affected by both short-term and chronic bortezomib treatments in Sensory ganglia neurons. Proteasome inhibition induces dose-dependent alterations in the architecture, positioning, shape and polarity of the neuronal nucleus. It also produces DNA damage without affecting neuronal survival, and severe disruption of the protein synthesis machinery at the central cytoplasm accompanied by decreased expression of the brain-derived neurotrophic factor. As a compensatory or adaptive survival response against proteotoxic stress caused by bortezomib treatment, Sensory neurons preserve basal levels of transcriptional activity, up-regulate the expression of proteasome subunit genes, and generate a new cytoplasmic perinuclear domain for protein synthesis. We propose that proteasome activity is crucial for controlling nuclear architecture, DNA repair and the organization of the protein synthesis machinery in Sensory neurons. These neurons are primary targets of bortezomib neurotoxicity, for which reason their dysfunction may contribute to the pathogenesis of the bortezomib-induced peripheral neuropathy in treated patients.
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Reactive nucleolar and Cajal body responses to proteasome inhibition in Sensory Ganglion neurons.
Biochimica et biophysica acta, 2013Co-Authors: Ana Palanca, Iñigo Casafont, Maria T. Berciano, Miguel LafargaAbstract:Abstract The dysfunction of the ubiquitin proteasome system has been related to a broad array of neurodegenerative disorders in which the accumulation of misfolded protein aggregates causes proteotoxicity. The ability of proteasome inhibitors to induce cell cycle arrest and apoptosis has emerged as a powerful strategy for cancer therapy. Bortezomib is a proteasome inhibitor used as an antineoplastic drug, although its neurotoxicity frequently causes a severe Sensory peripheral neuropathy. In this study we used a rat model of bortezomib treatment to study the nucleolar and Cajal body responses to the proteasome inhibition in Sensory Ganglion neurons that are major targets of bortezomib-induced neurotoxicity. Treatment with bortezomib induced dose-dependent dissociation of protein synthesis machinery (chromatolysis) and nuclear retention of poly(A) RNA granules resulting in neuronal dysfunction. However, as a compensatory response to the proteotoxic stress, both nucleoli and Cajal bodies exhibited reactive changes. These include an increase in the number and size of nucleoli, strong nucleolar incorporation of the RNA precursor 5′-fluorouridine, and increased expression of both 45S rRNA and genes encoding nucleolar proteins UBF, fibrillarin and B23. Taken together, these findings appear to reflect the activation of the nucleolar transcription in response to proteotoxic stress Furthermore, the number of Cajal bodies, a parameter related to transcriptional activity, increases upon proteasome inhibition. We propose that nucleoli and Cajal bodies are important targets in the signaling pathways that are activated by the proteotoxic stress response to proteasome inhibition. The coordinating activity of these two organelles in the production of snRNA, snoRNA and rRNA may contribute to neuronal survival after proteasome inhibition. This article is part of a Special Issue entitled: Role of the Nucleolus in Human Disease.
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Effect of ionizing radiation in Sensory Ganglion neurons: organization and dynamics of nuclear compartments of DNA damage/repair and their relationship with transcription and cell cycle.
Acta neuropathologica, 2011Co-Authors: Iñigo Casafont, Ana Palanca, Maria T. Berciano, Vanesa Lafarga, Miguel LafargaAbstract:Neurons are very sensitive to DNA damage induced by endogenous and exogenous genotoxic agents, as defective DNA repair can lead to neurodevelopmental disorders, brain tumors and neurodegenerative diseases with severe clinical manifestations. Understanding the impact of DNA damage/repair mechanisms on the nuclear organization, particularly on the regulation of transcription and cell cycle, is essential to know the pathophysiology of defective DNA repair syndromes. In this work, we study the nuclear architecture and spatiotemporal organization of chromatin compartments involved in the DNA damage response (DDR) in rat Sensory Ganglion neurons exposed to X-ray irradiation (IR). We demonstrate that the neuronal DDR involves the formation of two categories of DNA-damage processing chromatin compartments: transient, disappearing within the 1 day post-IR, and persistent, where unrepaired DNA is accumulated. Both compartments concentrate components of the DDR pathway, including γH2AX, pATM and 53BP1. Furthermore, DNA damage does not induce neuronal apoptosis but triggers the G0–G1 cell cycle phase transition, which is mediated by the activation of the ATM-p53 pathway and increased protein levels of p21 and cyclin D1. Moreover, the run on transcription assay reveals a severe inhibition of transcription at 0.5 h post-IR, followed by its rapid recovery over the 1 day post-IR in parallel with the progression of DNA repair. Therefore, the response of healthy neurons to DNA damage involves a transcription- and cell cycle-dependent but apoptosis-independent process. Furthermore, we propose that the segregation of unrepaired DNA in a few persistent chromatin compartments preserves genomic stability of undamaged DNA and the global transcription rate in neurons.
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effect of ionizing radiation in Sensory Ganglion neurons organization and dynamics of nuclear compartments of dna damage repair and their relationship with transcription and cell cycle
Acta Neuropathologica, 2011Co-Authors: Iñigo Casafont, Ana Palanca, Maria T. Berciano, Vanesa Lafarga, Miguel LafargaAbstract:Neurons are very sensitive to DNA damage induced by endogenous and exogenous genotoxic agents, as defective DNA repair can lead to neurodevelopmental disorders, brain tumors and neurodegenerative diseases with severe clinical manifestations. Understanding the impact of DNA damage/repair mechanisms on the nuclear organization, particularly on the regulation of transcription and cell cycle, is essential to know the pathophysiology of defective DNA repair syndromes. In this work, we study the nuclear architecture and spatiotemporal organization of chromatin compartments involved in the DNA damage response (DDR) in rat Sensory Ganglion neurons exposed to X-ray irradiation (IR). We demonstrate that the neuronal DDR involves the formation of two categories of DNA-damage processing chromatin compartments: transient, disappearing within the 1 day post-IR, and persistent, where unrepaired DNA is accumulated. Both compartments concentrate components of the DDR pathway, including γH2AX, pATM and 53BP1. Furthermore, DNA damage does not induce neuronal apoptosis but triggers the G0–G1 cell cycle phase transition, which is mediated by the activation of the ATM-p53 pathway and increased protein levels of p21 and cyclin D1. Moreover, the run on transcription assay reveals a severe inhibition of transcription at 0.5 h post-IR, followed by its rapid recovery over the 1 day post-IR in parallel with the progression of DNA repair. Therefore, the response of healthy neurons to DNA damage involves a transcription- and cell cycle-dependent but apoptosis-independent process. Furthermore, we propose that the segregation of unrepaired DNA in a few persistent chromatin compartments preserves genomic stability of undamaged DNA and the global transcription rate in neurons.
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pml bodies in reactive Sensory Ganglion neurons of the guillain barre syndrome
Neurobiology of Disease, 2004Co-Authors: Nuria T. Villagra, Iñigo Casafont, Miguel Lafarga, José Berciano, Marcos Altable, Joaquín Navascués, Maria T. BercianoAbstract:Abstract Acute inflammatory demyelinating polyneuropathy (AIDP) is a type of Guillain–Barre syndrome (GBS) characterized by primary nerve demyelination sometimes with secondary axonal degeneration. Studies on the fine structure of dorsal root ganglia in AIDP are lacking. Our aim was to investigate the cytology and nuclear organization of primary Sensory neurons in AIDP with axonal injury using ultrastructural and immunohistochemical analysis. The light cytology of the L5 dorsal Ganglion showed the characteristic findings of neuronal axonal reaction. The organization of chromatin, nucleolus, Cajal bodies, and nuclear pores corresponded to transcriptionally active neurons. However, the hallmark of the nuclear response to axonal injury was the formation of numerous nuclear bodies (NBs; 6.37 ± 0.6, in the AIDP, vs. 2.53 ± 0.2, in the control, mean ± SDM), identified as promyelocytic leukemia (PML) bodies by the presence of the protein PML. In addition to PML protein, nuclear bodies contained SUMO-1 and the transcriptional regulators CREB-binding protein (CBP) and glucocorticoid receptor (GR). The presence of proteasome 19S was also detected in some nuclear bodies. We suggest that neuronal PML bodies could regulate the nuclear concentration of active proteins, a process mediated by protein interactions with PML and SUMO-1 proteins. In the AIDP case, the proliferation of PML bodies may result from the overexpression of some nuclear proteins due to changes in gene expression associated with axonal injury.
