The Experts below are selected from a list of 23586 Experts worldwide ranked by ideXlab platform
Giampietro Schiavo - One of the best experts on this subject based on the ideXlab platform.
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altered Sensory Neuron development in cmt2d mice is site specific and linked to increased glyrs levels
Frontiers in Cellular Neuroscience, 2020Co-Authors: James N Sleigh, Giampietro Schiavo, Aleksandra M Mech, Tahmina Aktar, Yuxin ZhangAbstract:Dominant, missense mutations in the widely and constitutively expressed GARS1 gene cause peripheral neuropathy that usually begins in adolescence and principally impacts the upper limbs. Caused by a toxic gain-of-function in the encoded glycyl-tRNA synthetase (GlyRS) enzyme, the neuropathology appears to be independent of the canonical role of GlyRS in aminoacylation. Patients display progressive, life-long weakness and wasting of muscles in hands followed by feet, with frequently associated deficits in sensation. When dysfunction is observed in motor and Sensory nerves, there is a diagnosis of Charcot-Marie-Tooth disease type 2D (CMT2D), or distal hereditary motor neuropathy type V if the symptoms are purely motor. The cause of this varied Sensory involvement remains unresolved, as are the pathomechanisms underlying the selective neurodegeneration characteristic of the disease. We have previously identified in CMT2D mice that neuropathy-causing Gars mutations perturb Sensory Neuron fate and permit mutant GlyRS to aberrantly interact with neurotrophin receptors (Trks). Here, we extend this work by interrogating further the anatomy and function of the CMT2D Sensory nervous system in mutant Gars mice, obtaining several key results: (1) Sensory pathology is restricted to Neurons innervating the hindlimbs; (2) perturbation of Sensory development is not common to all mouse models of neuromuscular disease; (3) in vitro axonal transport of signaling endosomes is not impaired in afferent Neurons of all CMT2D mouse models; and (4) Gars expression is selectively elevated in a subset of Sensory Neurons and linked to Sensory developmental defects. These findings highlight the importance of comparative neurological assessment in mouse models of disease and shed light on key proposed neuropathogenic mechanisms in GARS1-linked neuropathy.
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a video protocol for rapid dissection of mouse dorsal root ganglia from defined spinal levels
BMC Research Notes, 2020Co-Authors: James N Sleigh, Steven J West, Giampietro SchiavoAbstract:Dorsal root ganglia (DRG) are heterogeneous assemblies of assorted Sensory Neuron cell bodies found in bilateral pairs at every level of the spinal column. Pseudounipolar afferent Neurons convert external stimuli from the environment into electrical signals that are retrogradely transmitted to the spinal cord dorsal horn. To do this, they extend single axons from their DRG-resident somas that then bifurcate and project both centrally and distally. DRG can be dissected from mice at embryonic stages and any age post-natally, and have been extensively used to study Sensory Neuron development and function, response to injury, and pathological processes in acquired and genetic diseases. We have previously published a step-by-step dissection method for the rapid isolation of post-natal mouse DRG. Here, the objective is to extend the protocol by providing training videos that showcase the dissection in fine detail and permit the extraction of ganglia from defined spinal levels. By following this method, the reader will be able to swiftly and accurately isolate specific lumbar, thoracic, and cervical DRG from mice. Dissected ganglia can then be used for RNA/protein analyses, subjected to immunohistochemical examination, and cultured as explants or dissociated primary Neurons, for in-depth investigations of Sensory Neuron biology.
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uba1 gars dependent pathways drive Sensory motor connectivity defects in spinal muscular atrophy
Brain, 2018Co-Authors: Hannah K. Shorrock, James N Sleigh, Dinja Van Der Hoorn, Penelope J Boyd, Maica Llavero Hurtado, Douglas J. Lamont, Brunhilde Wirth, Giampietro Schiavo, Thomas M. Wishart, Ewout J. N. GroenAbstract:Deafferentation of motor Neurons as a result of defective Sensory-motor connectivity is a critical early event in the pathogenesis of spinal muscular atrophy, but the underlying molecular pathways remain unknown. We show that restoration of ubiquitin-like modifier-activating enzyme 1 (UBA1) was sufficient to correct Sensory-motor connectivity in the spinal cord of mice with spinal muscular atrophy. Aminoacyl-tRNA synthetases, including GARS, were identified as downstream targets of UBA1. Regulation of GARS by UBA1 occurred via a non-canonical pathway independent of ubiquitylation. Dysregulation of UBA1/GARS pathways in spinal muscular atrophy mice disrupted Sensory Neuron fate, phenocopying GARS-dependent defects associated with Charcot-Marie-Tooth disease. Sensory Neuron fate was corrected following restoration of UBA1 expression and UBA1/GARS pathways in spinal muscular atrophy mice. We conclude that defective Sensory motor connectivity in spinal muscular atrophy results from perturbations in a UBA1/GARS pathway that modulates Sensory Neuron fate, thereby highlighting significant molecular and phenotypic overlap between spinal muscular atrophy and Charcot-Marie-Tooth disease.
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UBA1/GARS-dependent pathways drive Sensory-motor connectivity defects in spinal muscular atrophy
Brain : a journal of neurology, 2018Co-Authors: Hannah K. Shorrock, James N Sleigh, Dinja Van Der Hoorn, Penelope J Boyd, Maica Llavero Hurtado, Douglas J. Lamont, Brunhilde Wirth, Giampietro Schiavo, Thomas M. Wishart, Ewout J. N. GroenAbstract:Deafferentation of motor Neurons as a result of defective Sensory-motor connectivity is a critical early event in the pathogenesis of spinal muscular atrophy, but the underlying molecular pathways remain unknown. We show that restoration of ubiquitin-like modifier-activating enzyme 1 (UBA1) was sufficient to correct Sensory-motor connectivity in the spinal cord of mice with spinal muscular atrophy. Aminoacyl-tRNA synthetases, including GARS, were identified as downstream targets of UBA1. Regulation of GARS by UBA1 occurred via a non-canonical pathway independent of ubiquitylation. Dysregulation of UBA1/GARS pathways in spinal muscular atrophy mice disrupted Sensory Neuron fate, phenocopying GARS-dependent defects associated with Charcot-Marie-Tooth disease. Sensory Neuron fate was corrected following restoration of UBA1 expression and UBA1/GARS pathways in spinal muscular atrophy mice. We conclude that defective Sensory motor connectivity in spinal muscular atrophy results from perturbations in a UBA1/GARS pathway that modulates Sensory Neuron fate, thereby highlighting significant molecular and phenotypic overlap between spinal muscular atrophy and Charcot-Marie-Tooth disease.
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Sensory Neuron fate is developmentally perturbed by gars mutations causing human neuropathy
bioRxiv, 2016Co-Authors: James N Sleigh, John M Dawes, Steven J West, A Gomezmartin, Robert W Burgess, M Z Cader, Kevin Talbot, Emily Spaulding, David L H Bennett, Giampietro SchiavoAbstract:Charcot-Marie-Tooth disease type 2D (CMT2D) is a peripheral nerve disorder caused by dominant, toxic, gain-of-function mutations in the widely expressed, housekeeping gene, GARS. The mechanisms underlying selective nerve pathology in CMT2D remain unresolved, as does the cause of the mild-to-moderate Sensory involvement that distinguishes CMT2D from the allelic disorder distal spinal muscular atrophy type V. To elucidate the mechanism responsible for the underlying afferent nerve pathology, we examined the Sensory nervous system in CMT2D mice. We show that the equilibrium between functional subtypes of Sensory Neuron in dorsal root ganglia is distorted by Gars mutations, leading to Sensory defects in peripheral tissues and correlating with overall disease severity. CMT2D mice display changes in Sensory behaviour concordant with the afferent imbalance, which is present at birth and non-progressive, indicating that Sensory Neuron identity is prenatally perturbed and that a critical developmental insult is key to the afferent pathology. This suggests that both neurodevelopmental and neurodegenerative mechanisms contribute to CMT2D pathogenesis, and thus has profound implications for the timing of future therapeutic treatments.
James N Sleigh - One of the best experts on this subject based on the ideXlab platform.
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altered Sensory Neuron development in cmt2d mice is site specific and linked to increased glyrs levels
Frontiers in Cellular Neuroscience, 2020Co-Authors: James N Sleigh, Giampietro Schiavo, Aleksandra M Mech, Tahmina Aktar, Yuxin ZhangAbstract:Dominant, missense mutations in the widely and constitutively expressed GARS1 gene cause peripheral neuropathy that usually begins in adolescence and principally impacts the upper limbs. Caused by a toxic gain-of-function in the encoded glycyl-tRNA synthetase (GlyRS) enzyme, the neuropathology appears to be independent of the canonical role of GlyRS in aminoacylation. Patients display progressive, life-long weakness and wasting of muscles in hands followed by feet, with frequently associated deficits in sensation. When dysfunction is observed in motor and Sensory nerves, there is a diagnosis of Charcot-Marie-Tooth disease type 2D (CMT2D), or distal hereditary motor neuropathy type V if the symptoms are purely motor. The cause of this varied Sensory involvement remains unresolved, as are the pathomechanisms underlying the selective neurodegeneration characteristic of the disease. We have previously identified in CMT2D mice that neuropathy-causing Gars mutations perturb Sensory Neuron fate and permit mutant GlyRS to aberrantly interact with neurotrophin receptors (Trks). Here, we extend this work by interrogating further the anatomy and function of the CMT2D Sensory nervous system in mutant Gars mice, obtaining several key results: (1) Sensory pathology is restricted to Neurons innervating the hindlimbs; (2) perturbation of Sensory development is not common to all mouse models of neuromuscular disease; (3) in vitro axonal transport of signaling endosomes is not impaired in afferent Neurons of all CMT2D mouse models; and (4) Gars expression is selectively elevated in a subset of Sensory Neurons and linked to Sensory developmental defects. These findings highlight the importance of comparative neurological assessment in mouse models of disease and shed light on key proposed neuropathogenic mechanisms in GARS1-linked neuropathy.
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a video protocol for rapid dissection of mouse dorsal root ganglia from defined spinal levels
BMC Research Notes, 2020Co-Authors: James N Sleigh, Steven J West, Giampietro SchiavoAbstract:Dorsal root ganglia (DRG) are heterogeneous assemblies of assorted Sensory Neuron cell bodies found in bilateral pairs at every level of the spinal column. Pseudounipolar afferent Neurons convert external stimuli from the environment into electrical signals that are retrogradely transmitted to the spinal cord dorsal horn. To do this, they extend single axons from their DRG-resident somas that then bifurcate and project both centrally and distally. DRG can be dissected from mice at embryonic stages and any age post-natally, and have been extensively used to study Sensory Neuron development and function, response to injury, and pathological processes in acquired and genetic diseases. We have previously published a step-by-step dissection method for the rapid isolation of post-natal mouse DRG. Here, the objective is to extend the protocol by providing training videos that showcase the dissection in fine detail and permit the extraction of ganglia from defined spinal levels. By following this method, the reader will be able to swiftly and accurately isolate specific lumbar, thoracic, and cervical DRG from mice. Dissected ganglia can then be used for RNA/protein analyses, subjected to immunohistochemical examination, and cultured as explants or dissociated primary Neurons, for in-depth investigations of Sensory Neuron biology.
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uba1 gars dependent pathways drive Sensory motor connectivity defects in spinal muscular atrophy
Brain, 2018Co-Authors: Hannah K. Shorrock, James N Sleigh, Dinja Van Der Hoorn, Penelope J Boyd, Maica Llavero Hurtado, Douglas J. Lamont, Brunhilde Wirth, Giampietro Schiavo, Thomas M. Wishart, Ewout J. N. GroenAbstract:Deafferentation of motor Neurons as a result of defective Sensory-motor connectivity is a critical early event in the pathogenesis of spinal muscular atrophy, but the underlying molecular pathways remain unknown. We show that restoration of ubiquitin-like modifier-activating enzyme 1 (UBA1) was sufficient to correct Sensory-motor connectivity in the spinal cord of mice with spinal muscular atrophy. Aminoacyl-tRNA synthetases, including GARS, were identified as downstream targets of UBA1. Regulation of GARS by UBA1 occurred via a non-canonical pathway independent of ubiquitylation. Dysregulation of UBA1/GARS pathways in spinal muscular atrophy mice disrupted Sensory Neuron fate, phenocopying GARS-dependent defects associated with Charcot-Marie-Tooth disease. Sensory Neuron fate was corrected following restoration of UBA1 expression and UBA1/GARS pathways in spinal muscular atrophy mice. We conclude that defective Sensory motor connectivity in spinal muscular atrophy results from perturbations in a UBA1/GARS pathway that modulates Sensory Neuron fate, thereby highlighting significant molecular and phenotypic overlap between spinal muscular atrophy and Charcot-Marie-Tooth disease.
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UBA1/GARS-dependent pathways drive Sensory-motor connectivity defects in spinal muscular atrophy
Brain : a journal of neurology, 2018Co-Authors: Hannah K. Shorrock, James N Sleigh, Dinja Van Der Hoorn, Penelope J Boyd, Maica Llavero Hurtado, Douglas J. Lamont, Brunhilde Wirth, Giampietro Schiavo, Thomas M. Wishart, Ewout J. N. GroenAbstract:Deafferentation of motor Neurons as a result of defective Sensory-motor connectivity is a critical early event in the pathogenesis of spinal muscular atrophy, but the underlying molecular pathways remain unknown. We show that restoration of ubiquitin-like modifier-activating enzyme 1 (UBA1) was sufficient to correct Sensory-motor connectivity in the spinal cord of mice with spinal muscular atrophy. Aminoacyl-tRNA synthetases, including GARS, were identified as downstream targets of UBA1. Regulation of GARS by UBA1 occurred via a non-canonical pathway independent of ubiquitylation. Dysregulation of UBA1/GARS pathways in spinal muscular atrophy mice disrupted Sensory Neuron fate, phenocopying GARS-dependent defects associated with Charcot-Marie-Tooth disease. Sensory Neuron fate was corrected following restoration of UBA1 expression and UBA1/GARS pathways in spinal muscular atrophy mice. We conclude that defective Sensory motor connectivity in spinal muscular atrophy results from perturbations in a UBA1/GARS pathway that modulates Sensory Neuron fate, thereby highlighting significant molecular and phenotypic overlap between spinal muscular atrophy and Charcot-Marie-Tooth disease.
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trk receptor signaling and Sensory Neuron fate are perturbed in human neuropathy caused by gars mutations
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: James N Sleigh, John M Dawes, Steven J West, Emily L Spaulding, A Gomezmartin, Qinghai Zhang, Robert W Burgess, M Z Cader, Kevin Talbot, Yang XlAbstract:Charcot–Marie–Tooth disease type 2D (CMT2D) is a peripheral nerve disorder caused by dominant, toxic, gain-of-function mutations in the widely expressed, housekeeping gene, GARS. The mechanisms underlying selective nerve pathology in CMT2D remain unresolved, as does the cause of the mild-to-moderate Sensory involvement that distinguishes CMT2D from the allelic disorder distal spinal muscular atrophy type V. To elucidate the mechanism responsible for the underlying afferent nerve pathology, we examined the Sensory nervous system of CMT2D mice. We show that the equilibrium between functional subtypes of Sensory Neuron in dorsal root ganglia is distorted by Gars mutations, leading to Sensory defects in peripheral tissues and correlating with overall disease severity. CMT2D mice display changes in Sensory behavior concordant with the afferent imbalance, which is present at birth and nonprogressive, indicating that Sensory Neuron identity is prenatally perturbed and that a critical developmental insult is key to the afferent pathology. Through in vitro experiments, mutant, but not wild-type, GlyRS was shown to aberrantly interact with the Trk receptors and cause misactivation of Trk signaling, which is essential for Sensory Neuron differentiation and development. Together, this work suggests that both neurodevelopmental and neurodegenerative mechanisms contribute to CMT2D pathogenesis, and thus has profound implications for the timing of future therapeutic treatments.
John N Wood - One of the best experts on this subject based on the ideXlab platform.
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a Sensory Neuron specific proton gated ion channel
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Chihcheng Chen, Steven England, Armen N Akopian, John N WoodAbstract:Proton-gated channels expressed by Sensory Neurons are of particular interest because low pH causes pain. Two proton-gated channels, acid-sensing ionic channel (ASIC) and dorsal root ASIC (DRASIC), that are members of the amiloride-sensitive ENaC/Degenerin family are known to be expressed by Sensory Neurons. Here, we describe the cloning and characterization of an ASIC splice variant, ASIC-β, which contains a unique N-terminal 172 aa, as well as unique 5′ and 3′ untranslated sequences. ASIC-β, unlike ASIC and DRASIC, is found only in a subset of small and large diameter Sensory Neurons and is absent from sympathetic Neurons or the central nervous system. The patterns of expression of ASIC and ASIC-β transcripts in rat dorsal root ganglion Neurons are distinct. When expressed in COS-7 cells, ASIC-β forms a functional channel with electrophysiological properties distinct from ASIC and DRASIC. The pH dependency and sensitivity to amiloride of ASIC-β is similar to that described for ASIC, but unlike ASIC, the channel is not permeable to calcium, nor are ASIC-β-mediated currents inhibited by extracellular calcium. The unique distribution of ASIC-β suggests that it may play a specialized role in Sensory Neuron function.
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regulation of expression of the Sensory Neuron specific sodium channel sns in inflammatory and neuropathic pain
Molecular and Cellular Neuroscience, 1997Co-Authors: Kenji Okuse, Stephen B Mcmahon, Armen N Akopian, Sandra R Chaplan, David Z Luo, Nigel A Calcutt, Brian Scott, John N WoodAbstract:Increased voltage-gated sodium channel activity may contribute to the hyperexcitability of Sensory Neurons in inflammatory and neuropathic pain states. We examined the levels of the transcript encoding the tetrodotoxin-resistant sodium channel SNS in dorsal root ganglion Neurons in a range of inflammatory and neuropathic pain models in the rat. Local Freund's adjuvant or systemic nerve growth factor-induced inflammation did not substantially alter the total levels of SNS mRNA. When NGF-treated adult rat DRG Neurons in vitro were compared with NGF-depleted control Neurons, SNS total mRNA levels and the levels of membrane-associated immunoreactive SNS showed a small increase (17 and 25%, respectively), while CGRP levels increased fourfold. SNS expression is thus little dependent on NGF even though SNS transcript levels dropped by more than 60% 7-14 days after axotomy. In the streptozotocin diabetic rat SNS levels fell 25%, while in several manipulations of the L5/6 tight nerve ligation rat neuropathic pain model, SNS levels fell 40-80% in rat strains that are either susceptible or relatively resistant to the development of allodynia. Increased expression of SNS mRNA is thus unlikely to underlie Sensory Neuron hyperexcitability associated with inflammation, while lowered SNS transcript levels are associated with peripheral nerve damage.
Armen N Akopian - One of the best experts on this subject based on the ideXlab platform.
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a Sensory Neuron specific proton gated ion channel
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Chihcheng Chen, Steven England, Armen N Akopian, John N WoodAbstract:Proton-gated channels expressed by Sensory Neurons are of particular interest because low pH causes pain. Two proton-gated channels, acid-sensing ionic channel (ASIC) and dorsal root ASIC (DRASIC), that are members of the amiloride-sensitive ENaC/Degenerin family are known to be expressed by Sensory Neurons. Here, we describe the cloning and characterization of an ASIC splice variant, ASIC-β, which contains a unique N-terminal 172 aa, as well as unique 5′ and 3′ untranslated sequences. ASIC-β, unlike ASIC and DRASIC, is found only in a subset of small and large diameter Sensory Neurons and is absent from sympathetic Neurons or the central nervous system. The patterns of expression of ASIC and ASIC-β transcripts in rat dorsal root ganglion Neurons are distinct. When expressed in COS-7 cells, ASIC-β forms a functional channel with electrophysiological properties distinct from ASIC and DRASIC. The pH dependency and sensitivity to amiloride of ASIC-β is similar to that described for ASIC, but unlike ASIC, the channel is not permeable to calcium, nor are ASIC-β-mediated currents inhibited by extracellular calcium. The unique distribution of ASIC-β suggests that it may play a specialized role in Sensory Neuron function.
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a Sensory Neuron specific proton gated ion channel
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Chihcheng Chen, Steven England, Armen N Akopian, J WoodAbstract:Proton-gated channels expressed by Sensory Neurons are of particular interest because low pH causes pain. Two proton-gated channels, acid-sensing ionic channel (ASIC) and dorsal root ASIC (DRASIC), that are members of the amiloride-sensitive ENaC/Degenerin family are known to be expressed by Sensory Neurons. Here, we describe the cloning and characterization of an ASIC splice variant, ASIC-beta, which contains a unique N-terminal 172 aa, as well as unique 5' and 3' untranslated sequences. ASIC-beta, unlike ASIC and DRASIC, is found only in a subset of small and large diameter Sensory Neurons and is absent from sympathetic Neurons or the central nervous system. The patterns of expression of ASIC and ASIC-beta transcripts in rat dorsal root ganglion Neurons are distinct. When expressed in COS-7 cells, ASIC-beta forms a functional channel with electrophysiological properties distinct from ASIC and DRASIC. The pH dependency and sensitivity to amiloride of ASIC-beta is similar to that described for ASIC, but unlike ASIC, the channel is not permeable to calcium, nor are ASIC-beta-mediated currents inhibited by extracellular calcium. The unique distribution of ASIC-beta suggests that it may play a specialized role in Sensory Neuron function.
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regulation of expression of the Sensory Neuron specific sodium channel sns in inflammatory and neuropathic pain
Molecular and Cellular Neuroscience, 1997Co-Authors: Kenji Okuse, Stephen B Mcmahon, Armen N Akopian, Sandra R Chaplan, David Z Luo, Nigel A Calcutt, Brian Scott, John N WoodAbstract:Increased voltage-gated sodium channel activity may contribute to the hyperexcitability of Sensory Neurons in inflammatory and neuropathic pain states. We examined the levels of the transcript encoding the tetrodotoxin-resistant sodium channel SNS in dorsal root ganglion Neurons in a range of inflammatory and neuropathic pain models in the rat. Local Freund's adjuvant or systemic nerve growth factor-induced inflammation did not substantially alter the total levels of SNS mRNA. When NGF-treated adult rat DRG Neurons in vitro were compared with NGF-depleted control Neurons, SNS total mRNA levels and the levels of membrane-associated immunoreactive SNS showed a small increase (17 and 25%, respectively), while CGRP levels increased fourfold. SNS expression is thus little dependent on NGF even though SNS transcript levels dropped by more than 60% 7-14 days after axotomy. In the streptozotocin diabetic rat SNS levels fell 25%, while in several manipulations of the L5/6 tight nerve ligation rat neuropathic pain model, SNS levels fell 40-80% in rat strains that are either susceptible or relatively resistant to the development of allodynia. Increased expression of SNS mRNA is thus unlikely to underlie Sensory Neuron hyperexcitability associated with inflammation, while lowered SNS transcript levels are associated with peripheral nerve damage.
Clifford J. Woolf - One of the best experts on this subject based on the ideXlab platform.
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diversity of expression of the Sensory Neuron specific ttx resistant voltage gated sodium ion channels sns and sns2
Molecular and Cellular Neuroscience, 2000Co-Authors: Fumimasa Amaya, Michael Costigan, Richard J Mannion, Isabelle Decosterd, Tarek A Samad, C Plumpton, Simon Tate, Clifford J. WoolfAbstract:The differential distribution of two tetrodotoxin resistant (TTXr) voltage-gated sodium channels SNS (PN3) and SNS2 (NaN) in rat primary Sensory Neurons has been investigated. Both channels are Sensory Neuron specific with SNS2 restricted entirely to those small dorsal root ganglion (DRG) cells with unmyelinated axons (C-fibers). SNS, in contrast, is expressed both in small C-fiber DRG cells and in 10% of cells with myelinated axons (A-fibers). All SNS expressing A-fiber cells are Trk-A positive and many express the vanilloid-like receptor VRL1. About half of C-fiber DRG Neurons express either SNS or SNS2, and in most, the channels are colocalized. SNS and SNS2 are found both in NGF-responsive and GDNF-responsive C-fibers and many of these cells also express the capsaicin receptor VR1. A very small proportion of small DRG cells express either only SNS or only SNS2. At least four different classes of A- and C-fiber DRG Neurons exist, therefore, with respect to expression of these sodium channels.
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a role for hsp27 in Sensory Neuron survival
The Journal of Neuroscience, 1999Co-Authors: Susan E Lewis, Michael Costigan, Richard J Mannion, Fletcher A White, Richard E Coggeshall, Simon Beggs, Jody L Martin, Wolfgang H. Dillmann, Clifford J. WoolfAbstract:Peripheral nerve injury in neonatal rats results in the death of the majority of the axotomized Sensory Neurons by 7 d after injury. In adult animals, however, all Sensory Neurons survive for at least 4 months after axotomy. How Sensory Neurons acquire the capacity to survive axonal injury is not known. Here we describe how the expression of the small heat shock protein 27 (HSP27) is correlated with Neuronal survival after axotomy in vivo and after NGF withdrawal in vitro. The number of HSP27-immunoreactive Neurons in the L4 DRG is low at birth and does not change significantly for 21 d after postnatal day 0 (P0) sciatic nerve axotomy. In contrast, in the adult all axotomized Neurons begin to express HSP27. One week after P0 sciatic nerve section the total number of Neurons in the L4 DRG is dramatically reduced, but all surviving axotomized Neurons, as identified by c-jun immunoreactivity, are immunoreactive for HSP27. In addition, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling reveals that very few HSP27-expressing Neurons are dying 48 hr after neonatal axotomy. In vitro , a similar correlation exists between HSP27 expression and survival; in P0 DRG cultures, Neurons that express HSP27 preferentially survive NGF withdrawal. Finally, overexpression of human HSP27 in neonatal rat Sensory and sympathetic Neurons significantly increases survival after NGF withdrawal, with nearly twice as many Neurons surviving at 48 hr. Together these results suggest that HSP27 in Sensory Neurons plays a role in promoting survival after axotomy or neurotrophin withdrawal.
