The Experts below are selected from a list of 75 Experts worldwide ranked by ideXlab platform
John P. Crow - One of the best experts on this subject based on the ideXlab platform.
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paradoxical roles of serine racemase and d serine in the g93a mSOD1 Mouse model of amyotrophic lateral sclerosis
Journal of Neurochemistry, 2012Co-Authors: Misty M. Thompson, John C. Marecki, Stéphane Marinesco, Viviane Labrie, John C. Roder, Steven W. Barger, John P. CrowAbstract:J. Neurochem. (2012) 120, 598–610. Abstract d-Serine is an endogenous neurotransmitter that binds to the NMDA receptor, thereby increasing the affinity for glutamate, and the potential for excitotoxicity. The primary source of d-serine in vivo is enzymatic racemization by serine racemase (SR). Regulation of d-serine in vivo is poorly understood, but is thought to involve a combination of controlled production, synaptic reuptake by transporters, and intracellular degradation by d-amino acid oxidase (DAO). However, SR itself possesses a well-characterized eliminase activity, which effectively degrades d-serine as well. d-Serine is increased two-fold in spinal cords of G93A Cu,Zn-superoxide dismutase (SOD1) mice – the standard model of amyotrophic lateral sclerosis (ALS). ALS mice with SR disruption show earlier symptom onset, but survive longer (progression phase is slowed), in an SR-dependent manner. Paradoxically, administration of d-serine to ALS mice dramatically lowers cord levels of d-serine, leading to changes in the onset and survival very similar to SR deletion. d-Serine treatment also increases cord levels of the alanine–serine–cysteine transporter 1 (Asc-1). Although the mechanism by which SOD1 mutations increases d-serine is not known, these results strongly suggest that SR and d-serine are fundamentally involved in both the pre-symptomatic and progression phases of disease, and offer a direct link between mutant SOD1 and a glial-derived toxic mediator.
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Paradoxical roles of serine racemase and d‐serine in the G93A mSOD1 Mouse model of amyotrophic lateral sclerosis
Journal of neurochemistry, 2012Co-Authors: Misty M. Thompson, John C. Marecki, Stéphane Marinesco, Viviane Labrie, John C. Roder, Steven W. Barger, John P. CrowAbstract:J. Neurochem. (2012) 120, 598–610. Abstract d-Serine is an endogenous neurotransmitter that binds to the NMDA receptor, thereby increasing the affinity for glutamate, and the potential for excitotoxicity. The primary source of d-serine in vivo is enzymatic racemization by serine racemase (SR). Regulation of d-serine in vivo is poorly understood, but is thought to involve a combination of controlled production, synaptic reuptake by transporters, and intracellular degradation by d-amino acid oxidase (DAO). However, SR itself possesses a well-characterized eliminase activity, which effectively degrades d-serine as well. d-Serine is increased two-fold in spinal cords of G93A Cu,Zn-superoxide dismutase (SOD1) mice – the standard model of amyotrophic lateral sclerosis (ALS). ALS mice with SR disruption show earlier symptom onset, but survive longer (progression phase is slowed), in an SR-dependent manner. Paradoxically, administration of d-serine to ALS mice dramatically lowers cord levels of d-serine, leading to changes in the onset and survival very similar to SR deletion. d-Serine treatment also increases cord levels of the alanine–serine–cysteine transporter 1 (Asc-1). Although the mechanism by which SOD1 mutations increases d-serine is not known, these results strongly suggest that SR and d-serine are fundamentally involved in both the pre-symptomatic and progression phases of disease, and offer a direct link between mutant SOD1 and a glial-derived toxic mediator.
Kathryn J. Jones - One of the best experts on this subject based on the ideXlab platform.
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CD4 + T Cells and Neuroprotection: Relevance to Motoneuron Injury and Disease
Journal of Neuroimmune Pharmacology, 2015Co-Authors: Kathryn J. Jones, Amy E. Lovett-racke, Chandler L. Walker, Virginia M SandersAbstract:We have established a physiologically relevant mechanism of CD4+ T cell-mediated neuroprotection involving axotomized wildtype (WT) Mouse facial motoneurons (FMN) with significance in the treatment of amyotrophic lateral sclerosis (ALS), a fatal MN disease. Use of the transgenic Mouse model of ALS involving expression of human mutant superoxide dismutase genes (SOD1^G93A; abbreviated here as mSOD1) has accelerated basic ALS research. Superimposition of facial nerve axotomy (FNA) on the mSOD1 Mouse during pre-symptomatic stages indicates that they behave like immunodeficient mice in terms of increased FMN loss and decreased functional recovery, through a mechanism that, paradoxically, is not inherent within the MN itself, but, instead, involves a defect in peripheral immune: CNS glial cell interactions. Our goal is to utilize our WT Mouse model of immune-mediated neuroprotection after FNA as a template to elucidate how a malfunctioning peripheral immune system contributes to motoneuron cell loss in the mSOD1 Mouse. This review will discuss potential immune defects in ALS, as well as provide an up-to-date understanding of how the CD4+ effector T cells provide neuroprotection to motoneurons through regulation of the central microglial and astrocytic response to injury. We will discuss an IL-10 cascade within the facial nucleus that requires a functional CD4+ T cell trigger for activation. The review will discuss the role of T cells in ALS, and our recent reconstitution experiments utilizing our model of T cell-mediated neuroprotection in WT vs mSOD1 mice after FNA. Identification of defects in neural:immune interactions could provide targets for therapeutic intervention in ALS.
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CD4 + T Cells and Neuroprotection: Relevance to Motoneuron Injury and Disease.
Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 2015Co-Authors: Kathryn J. Jones, Amy E. Lovett-racke, Chandler L. Walker, Virginia M SandersAbstract:We have established a physiologically relevant mechanism of CD4+ T cell-mediated neuroprotection involving axotomized wildtype (WT) Mouse facial motoneurons (FMN) with significance in the treatment of amyotrophic lateral sclerosis (ALS), a fatal MN disease. Use of the transgenic Mouse model of ALS involving expression of human mutant superoxide dismutase genes (SOD1G93A; abbreviated here as mSOD1) has accelerated basic ALS research. Superimposition of facial nerve axotomy (FNA) on the mSOD1 Mouse during pre-symptomatic stages indicates that they behave like immunodeficient mice in terms of increased FMN loss and decreased functional recovery, through a mechanism that, paradoxically, is not inherent within the MN itself, but, instead, involves a defect in peripheral immune: CNS glial cell interactions. Our goal is to utilize our WT Mouse model of immune-mediated neuroprotection after FNA as a template to elucidate how a malfunctioning peripheral immune system contributes to motoneuron cell loss in the mSOD1 Mouse. This review will discuss potential immune defects in ALS, as well as provide an up-to-date understanding of how the CD4+ effector T cells provide neuroprotection to motoneurons through regulation of the central microglial and astrocytic response to injury. We will discuss an IL-10 cascade within the facial nucleus that requires a functional CD4+ T cell trigger for activation. The review will discuss the role of T cells in ALS, and our recent reconstitution experiments utilizing our model of T cell-mediated neuroprotection in WT vs mSOD1 mice after FNA. Identification of defects in neural:immune interactions could provide targets for therapeutic intervention in ALS.
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Identification of B6SJL mSOD1G93A Mouse subgroups with different disease progression rates
The Journal of comparative neurology, 2015Co-Authors: Melissa M Haulcomb, Kathryn P Mcmillan, Whitney M Miller, Virginia M Sanders, Nichole A. Mesnard-hoaglin, Richard J. Batka, Rena M. Meadows, Todd J. Brown, Kathryn J. JonesAbstract:Disease progression rates among patients with amyotrophic lateral sclerosis (ALS) vary greatly. Although the majority of affected individuals survive 3–5 years following diagnosis, some subgroups experience a more rapidly progressing form, surviving less than 1 year, and other subgroups experience slowly progressing forms, surviving nearly 50 years. Genetic heterogeneity and environmental factors pose significant barriers in investigating patient progression rates. Similar to the case for humans, variation in survival within the mSOD1 Mouse has been well documented, but different progression rates have not been investigated. The present study identifies two subgroups of B6SJL mSOD1G93A mice with different disease progression rates, a fast progression group (FPG) and slow progression group, as evidenced by differences in the rate of motor function decline. In addition, increased disease-associated gene expression within the FPG facial motor nucleus confirmed the presence of a more severe phenotype. We hypothesize that a more severe disease phenotype could be the result of 1) an earlier onset of axonal disconnection with a consistent degeneration rate or 2) a more severe or accelerated degenerative process. We performed a facial nerve transection axotomy in both mSOD1 subgroups prior to disease onset as a method to standardize the axonal disconnection. Instead of leading to comparable gene expression in both subgroups, this standardization did not eliminate the severe phenotype in the FPG facial nucleus, suggesting that the FPG phenotype is the result of a more severe or accelerated degenerative process. We theorize that these mSOD1 subgroups are representative of the rapid and slow disease phenotypes often experienced in ALS. J. Comp. Neurol. 523:2752–2768, 2015. © 2015 Wiley Periodicals, Inc.
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Delayed functional recovery in presymptomatic mSOD1G93A mice following facial nerve crush axotomy.
Journal of neurodegeneration & regeneration, 2013Co-Authors: Nichole A. Mesnard, Virginia M Sanders, Melissa M Haulcomb, Lisa Tanzer, Kathryn J. JonesAbstract:Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving progressive loss of motoneurons (MN). Axonal pathology and presynaptic deafferentation precede MN degeneration during disease progression in patients and the ALS Mouse model (mSOD1). Previously, we determined that a functional adaptive immune response is required for complete functional recovery following a facial nerve crush axotomy in wild-type (WT) mice. In this study, we investigated the effects of facial nerve crush axotomy on functional recovery and facial MN survival in presymptomatic mSOD1 mice, relative to WT mice. The results indicate that functional recovery and facial MN survival levels are significantly reduced in presymptomatic mSOD1, relative to WT, and similar to what has previously been observed in immunodeficient mice. It is concluded that a potential immune system defect exists in the mSOD1 Mouse that negatively impacts neuronal survival and regeneration following target disconnection associated with peripheral nerve axotomy. Keywords: Motoneuron survival, Functional recovery, Axotomy, SOD1, ALS DOI:10.5055/jndr.2013.0009
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Peripheral Immune Cell Functionality in Amyotrophic Lateral Sclerosis (P03.184)
Neurology, 2012Co-Authors: Nichole Mesnard, Thirupatthi Muthusamy, Jian Rong Sheng, Bellur S Prabhakar, Julie Rowin, Kathryn J. Jones, Matthew N. MeriggioliAbstract:Objective: To investigate the functionality of circulating immune cells in ALS patients. Background Amyotrophic lateral sclerosis (ALS) axonal pathology precedes motoneuron degeneration during disease progression in patients and the mSOD1 Mouse model. We and others have shown that a functional immune system is neuroprotective in mSOD1 mice, enhancing survival and promoting facial motoneuron (FMN) survival levels after axotomy. Increased levels of FMN loss after axotomy were seen in immunodeficient mice, but wildtype levels of FMN survival could be restored by adoptively transferring wildtype splenocytes or CD4+ T cells prior to axotomy. Interestingly, the adoptive transfer of mSOD1 whole splenocytes did not rescue axotomy-induced FMN death in immunodeficient mice, but isolated CD4 + T cells (from the splenocyte population) effectively mediated neuroprotection to similar levels as wildtype CD4 + T cells, suggesting that the defect in immune neuroprotection was NOT explained by a functional defect in CD4 + T cells. Previous studies examining the peripheral immune compartment in ALS patients have yielded varied results regarding levels/function of CD4 + T cells. Based on the results above, we hypothesize that the peripheral immune microenvironment in ALS activates CD4 + T cells early on, but the neuroprotective effects of certain T cell subsets are subsequently inhibited by non-Tcell components of the immune system. Design/Methods: In vitro T cell proliferation assays were utilized to assess the function of ALS T cell subsets activated with anti-CD3 stimulation and compared to controls. Results: ALS CD4 + T cell subsets maintain their functional and proliferative capabilities when removed from the ALS microenvironment and activated polyclonally. No differences in T regulatory cell function or FoxP3 expression were detected in ALS samples compared to controls. Conclusions: ALS CD4 + T cells function normally in response to polyclonal stimulation in vitro , suggesting that other components of the ALS immune system (B cells, dendritic cells, or macrophages) underlie the defect in neuroprotective CD4 + T cell functionality. Supported by: The ALS Association (JR). Disclosure: Dr. Mesnard has nothing to disclose. Dr. Muthusamy has nothing to disclose. Dr. Xin has nothing to disclose. Dr. Sheng has nothing to disclose. Dr. Jones has received research support from Veterans Affairs, the National Institutes of Health, and the Les Turneer ALS Foundation. Dr. Prabhakar has received personal compensation for activities with Gliknik Inc. as a consultant.Dr. Prabhakar has received research support from NIH. Dr. Rowin has nothing to disclose. Dr. Meriggioli has received personal compensation for activities with Athena Diagnostics, Talecris Biotherapeutics, Gliknik, and Celegene Corporation. Dr. Meriggioli receives patent payments for a patent on bispecific antibody coated dendritic cells. Dr. Meriggioli has received research support from the NIH/NINDS and the Muscular Dystrophy Association.
Virginia M Sanders - One of the best experts on this subject based on the ideXlab platform.
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impact of peripheral immune status on central molecular responses to facial nerve axotomy
Brain Behavior and Immunity, 2018Co-Authors: Deborah O Setter, Elizabeth M Runge, Nicole D Schartz, Felicia M Kennedy, Brandon L Brown, Kathryn P Mcmillan, Whitney M Miller, Kishan M Shah, Melissa M Haulcomb, Virginia M SandersAbstract:Abstract When facial nerve axotomy (FNA) is performed on immunodeficient recombinase activating gene-2 knockout (RAG-2−/−) mice, there is greater facial motoneuron (FMN) death relative to wild type (WT) mice. Reconstituting RAG-2−/− mice with whole splenocytes rescues FMN survival after FNA, and CD4+ T cells specifically drive immune-mediated neuroprotection. Evidence suggests that immunodysregulation may contribute to motoneuron death in amyotrophic lateral sclerosis (ALS). Immunoreconstitution of RAG-2−/− mice with lymphocytes from the mutant superoxide dismutase (mSOD1) Mouse model of ALS revealed that the mSOD1 whole splenocyte environment suppresses mSOD1 CD4+ T cell-mediated neuroprotection after FNA. The objective of the current study was to characterize the effect of CD4+ T cells on the central molecular response to FNA and then identify if mSOD1 whole splenocytes blocked these regulatory pathways. Gene expression profiles of the axotomized facial motor nucleus were assessed from RAG-2−/− mice immunoreconstituted with either CD4+ T cells or whole splenocytes from WT or mSOD1 donors. The findings indicate that immunodeficient mice have suppressed glial activation after axotomy, and cell transfer of WT CD4+ T cells rescues microenvironment responses. Additionally, mSOD1 whole splenocyte recipients exhibit an increased astrocyte activation response to FNA. In RAG-2−/− + mSOD1 whole splenocyte mice, an elevation of motoneuron-specific Fas cell death pathways is also observed. Altogether, these findings suggest that mSOD1 whole splenocytes do not suppress mSOD1 CD4+ T cell regulation of the microenvironment, and instead, mSOD1 whole splenocytes may promote motoneuron death by either promoting a neurotoxic astrocyte phenotype or inducing Fas-mediated cell death pathways. This study demonstrates that peripheral immune status significantly affects central responses to nerve injury. Future studies will elucidate the mechanisms by which mSOD1 whole splenocytes promote cell death and if inhibiting this mechanism can preserve motoneuron survival in injury and disease.
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CD4 + T Cells and Neuroprotection: Relevance to Motoneuron Injury and Disease
Journal of Neuroimmune Pharmacology, 2015Co-Authors: Kathryn J. Jones, Amy E. Lovett-racke, Chandler L. Walker, Virginia M SandersAbstract:We have established a physiologically relevant mechanism of CD4+ T cell-mediated neuroprotection involving axotomized wildtype (WT) Mouse facial motoneurons (FMN) with significance in the treatment of amyotrophic lateral sclerosis (ALS), a fatal MN disease. Use of the transgenic Mouse model of ALS involving expression of human mutant superoxide dismutase genes (SOD1^G93A; abbreviated here as mSOD1) has accelerated basic ALS research. Superimposition of facial nerve axotomy (FNA) on the mSOD1 Mouse during pre-symptomatic stages indicates that they behave like immunodeficient mice in terms of increased FMN loss and decreased functional recovery, through a mechanism that, paradoxically, is not inherent within the MN itself, but, instead, involves a defect in peripheral immune: CNS glial cell interactions. Our goal is to utilize our WT Mouse model of immune-mediated neuroprotection after FNA as a template to elucidate how a malfunctioning peripheral immune system contributes to motoneuron cell loss in the mSOD1 Mouse. This review will discuss potential immune defects in ALS, as well as provide an up-to-date understanding of how the CD4+ effector T cells provide neuroprotection to motoneurons through regulation of the central microglial and astrocytic response to injury. We will discuss an IL-10 cascade within the facial nucleus that requires a functional CD4+ T cell trigger for activation. The review will discuss the role of T cells in ALS, and our recent reconstitution experiments utilizing our model of T cell-mediated neuroprotection in WT vs mSOD1 mice after FNA. Identification of defects in neural:immune interactions could provide targets for therapeutic intervention in ALS.
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CD4 + T Cells and Neuroprotection: Relevance to Motoneuron Injury and Disease.
Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 2015Co-Authors: Kathryn J. Jones, Amy E. Lovett-racke, Chandler L. Walker, Virginia M SandersAbstract:We have established a physiologically relevant mechanism of CD4+ T cell-mediated neuroprotection involving axotomized wildtype (WT) Mouse facial motoneurons (FMN) with significance in the treatment of amyotrophic lateral sclerosis (ALS), a fatal MN disease. Use of the transgenic Mouse model of ALS involving expression of human mutant superoxide dismutase genes (SOD1G93A; abbreviated here as mSOD1) has accelerated basic ALS research. Superimposition of facial nerve axotomy (FNA) on the mSOD1 Mouse during pre-symptomatic stages indicates that they behave like immunodeficient mice in terms of increased FMN loss and decreased functional recovery, through a mechanism that, paradoxically, is not inherent within the MN itself, but, instead, involves a defect in peripheral immune: CNS glial cell interactions. Our goal is to utilize our WT Mouse model of immune-mediated neuroprotection after FNA as a template to elucidate how a malfunctioning peripheral immune system contributes to motoneuron cell loss in the mSOD1 Mouse. This review will discuss potential immune defects in ALS, as well as provide an up-to-date understanding of how the CD4+ effector T cells provide neuroprotection to motoneurons through regulation of the central microglial and astrocytic response to injury. We will discuss an IL-10 cascade within the facial nucleus that requires a functional CD4+ T cell trigger for activation. The review will discuss the role of T cells in ALS, and our recent reconstitution experiments utilizing our model of T cell-mediated neuroprotection in WT vs mSOD1 mice after FNA. Identification of defects in neural:immune interactions could provide targets for therapeutic intervention in ALS.
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Identification of B6SJL mSOD1G93A Mouse subgroups with different disease progression rates
The Journal of comparative neurology, 2015Co-Authors: Melissa M Haulcomb, Kathryn P Mcmillan, Whitney M Miller, Virginia M Sanders, Nichole A. Mesnard-hoaglin, Richard J. Batka, Rena M. Meadows, Todd J. Brown, Kathryn J. JonesAbstract:Disease progression rates among patients with amyotrophic lateral sclerosis (ALS) vary greatly. Although the majority of affected individuals survive 3–5 years following diagnosis, some subgroups experience a more rapidly progressing form, surviving less than 1 year, and other subgroups experience slowly progressing forms, surviving nearly 50 years. Genetic heterogeneity and environmental factors pose significant barriers in investigating patient progression rates. Similar to the case for humans, variation in survival within the mSOD1 Mouse has been well documented, but different progression rates have not been investigated. The present study identifies two subgroups of B6SJL mSOD1G93A mice with different disease progression rates, a fast progression group (FPG) and slow progression group, as evidenced by differences in the rate of motor function decline. In addition, increased disease-associated gene expression within the FPG facial motor nucleus confirmed the presence of a more severe phenotype. We hypothesize that a more severe disease phenotype could be the result of 1) an earlier onset of axonal disconnection with a consistent degeneration rate or 2) a more severe or accelerated degenerative process. We performed a facial nerve transection axotomy in both mSOD1 subgroups prior to disease onset as a method to standardize the axonal disconnection. Instead of leading to comparable gene expression in both subgroups, this standardization did not eliminate the severe phenotype in the FPG facial nucleus, suggesting that the FPG phenotype is the result of a more severe or accelerated degenerative process. We theorize that these mSOD1 subgroups are representative of the rapid and slow disease phenotypes often experienced in ALS. J. Comp. Neurol. 523:2752–2768, 2015. © 2015 Wiley Periodicals, Inc.
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Delayed functional recovery in presymptomatic mSOD1G93A mice following facial nerve crush axotomy.
Journal of neurodegeneration & regeneration, 2013Co-Authors: Nichole A. Mesnard, Virginia M Sanders, Melissa M Haulcomb, Lisa Tanzer, Kathryn J. JonesAbstract:Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving progressive loss of motoneurons (MN). Axonal pathology and presynaptic deafferentation precede MN degeneration during disease progression in patients and the ALS Mouse model (mSOD1). Previously, we determined that a functional adaptive immune response is required for complete functional recovery following a facial nerve crush axotomy in wild-type (WT) mice. In this study, we investigated the effects of facial nerve crush axotomy on functional recovery and facial MN survival in presymptomatic mSOD1 mice, relative to WT mice. The results indicate that functional recovery and facial MN survival levels are significantly reduced in presymptomatic mSOD1, relative to WT, and similar to what has previously been observed in immunodeficient mice. It is concluded that a potential immune system defect exists in the mSOD1 Mouse that negatively impacts neuronal survival and regeneration following target disconnection associated with peripheral nerve axotomy. Keywords: Motoneuron survival, Functional recovery, Axotomy, SOD1, ALS DOI:10.5055/jndr.2013.0009
John C. Roder - One of the best experts on this subject based on the ideXlab platform.
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paradoxical roles of serine racemase and d serine in the g93a mSOD1 Mouse model of amyotrophic lateral sclerosis
Journal of Neurochemistry, 2012Co-Authors: Misty M. Thompson, John C. Marecki, Stéphane Marinesco, Viviane Labrie, John C. Roder, Steven W. Barger, John P. CrowAbstract:J. Neurochem. (2012) 120, 598–610. Abstract d-Serine is an endogenous neurotransmitter that binds to the NMDA receptor, thereby increasing the affinity for glutamate, and the potential for excitotoxicity. The primary source of d-serine in vivo is enzymatic racemization by serine racemase (SR). Regulation of d-serine in vivo is poorly understood, but is thought to involve a combination of controlled production, synaptic reuptake by transporters, and intracellular degradation by d-amino acid oxidase (DAO). However, SR itself possesses a well-characterized eliminase activity, which effectively degrades d-serine as well. d-Serine is increased two-fold in spinal cords of G93A Cu,Zn-superoxide dismutase (SOD1) mice – the standard model of amyotrophic lateral sclerosis (ALS). ALS mice with SR disruption show earlier symptom onset, but survive longer (progression phase is slowed), in an SR-dependent manner. Paradoxically, administration of d-serine to ALS mice dramatically lowers cord levels of d-serine, leading to changes in the onset and survival very similar to SR deletion. d-Serine treatment also increases cord levels of the alanine–serine–cysteine transporter 1 (Asc-1). Although the mechanism by which SOD1 mutations increases d-serine is not known, these results strongly suggest that SR and d-serine are fundamentally involved in both the pre-symptomatic and progression phases of disease, and offer a direct link between mutant SOD1 and a glial-derived toxic mediator.
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Paradoxical roles of serine racemase and d‐serine in the G93A mSOD1 Mouse model of amyotrophic lateral sclerosis
Journal of neurochemistry, 2012Co-Authors: Misty M. Thompson, John C. Marecki, Stéphane Marinesco, Viviane Labrie, John C. Roder, Steven W. Barger, John P. CrowAbstract:J. Neurochem. (2012) 120, 598–610. Abstract d-Serine is an endogenous neurotransmitter that binds to the NMDA receptor, thereby increasing the affinity for glutamate, and the potential for excitotoxicity. The primary source of d-serine in vivo is enzymatic racemization by serine racemase (SR). Regulation of d-serine in vivo is poorly understood, but is thought to involve a combination of controlled production, synaptic reuptake by transporters, and intracellular degradation by d-amino acid oxidase (DAO). However, SR itself possesses a well-characterized eliminase activity, which effectively degrades d-serine as well. d-Serine is increased two-fold in spinal cords of G93A Cu,Zn-superoxide dismutase (SOD1) mice – the standard model of amyotrophic lateral sclerosis (ALS). ALS mice with SR disruption show earlier symptom onset, but survive longer (progression phase is slowed), in an SR-dependent manner. Paradoxically, administration of d-serine to ALS mice dramatically lowers cord levels of d-serine, leading to changes in the onset and survival very similar to SR deletion. d-Serine treatment also increases cord levels of the alanine–serine–cysteine transporter 1 (Asc-1). Although the mechanism by which SOD1 mutations increases d-serine is not known, these results strongly suggest that SR and d-serine are fundamentally involved in both the pre-symptomatic and progression phases of disease, and offer a direct link between mutant SOD1 and a glial-derived toxic mediator.
Misty M. Thompson - One of the best experts on this subject based on the ideXlab platform.
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paradoxical roles of serine racemase and d serine in the g93a mSOD1 Mouse model of amyotrophic lateral sclerosis
Journal of Neurochemistry, 2012Co-Authors: Misty M. Thompson, John C. Marecki, Stéphane Marinesco, Viviane Labrie, John C. Roder, Steven W. Barger, John P. CrowAbstract:J. Neurochem. (2012) 120, 598–610. Abstract d-Serine is an endogenous neurotransmitter that binds to the NMDA receptor, thereby increasing the affinity for glutamate, and the potential for excitotoxicity. The primary source of d-serine in vivo is enzymatic racemization by serine racemase (SR). Regulation of d-serine in vivo is poorly understood, but is thought to involve a combination of controlled production, synaptic reuptake by transporters, and intracellular degradation by d-amino acid oxidase (DAO). However, SR itself possesses a well-characterized eliminase activity, which effectively degrades d-serine as well. d-Serine is increased two-fold in spinal cords of G93A Cu,Zn-superoxide dismutase (SOD1) mice – the standard model of amyotrophic lateral sclerosis (ALS). ALS mice with SR disruption show earlier symptom onset, but survive longer (progression phase is slowed), in an SR-dependent manner. Paradoxically, administration of d-serine to ALS mice dramatically lowers cord levels of d-serine, leading to changes in the onset and survival very similar to SR deletion. d-Serine treatment also increases cord levels of the alanine–serine–cysteine transporter 1 (Asc-1). Although the mechanism by which SOD1 mutations increases d-serine is not known, these results strongly suggest that SR and d-serine are fundamentally involved in both the pre-symptomatic and progression phases of disease, and offer a direct link between mutant SOD1 and a glial-derived toxic mediator.
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Paradoxical roles of serine racemase and d‐serine in the G93A mSOD1 Mouse model of amyotrophic lateral sclerosis
Journal of neurochemistry, 2012Co-Authors: Misty M. Thompson, John C. Marecki, Stéphane Marinesco, Viviane Labrie, John C. Roder, Steven W. Barger, John P. CrowAbstract:J. Neurochem. (2012) 120, 598–610. Abstract d-Serine is an endogenous neurotransmitter that binds to the NMDA receptor, thereby increasing the affinity for glutamate, and the potential for excitotoxicity. The primary source of d-serine in vivo is enzymatic racemization by serine racemase (SR). Regulation of d-serine in vivo is poorly understood, but is thought to involve a combination of controlled production, synaptic reuptake by transporters, and intracellular degradation by d-amino acid oxidase (DAO). However, SR itself possesses a well-characterized eliminase activity, which effectively degrades d-serine as well. d-Serine is increased two-fold in spinal cords of G93A Cu,Zn-superoxide dismutase (SOD1) mice – the standard model of amyotrophic lateral sclerosis (ALS). ALS mice with SR disruption show earlier symptom onset, but survive longer (progression phase is slowed), in an SR-dependent manner. Paradoxically, administration of d-serine to ALS mice dramatically lowers cord levels of d-serine, leading to changes in the onset and survival very similar to SR deletion. d-Serine treatment also increases cord levels of the alanine–serine–cysteine transporter 1 (Asc-1). Although the mechanism by which SOD1 mutations increases d-serine is not known, these results strongly suggest that SR and d-serine are fundamentally involved in both the pre-symptomatic and progression phases of disease, and offer a direct link between mutant SOD1 and a glial-derived toxic mediator.