Chapter 26 Inactivation of intracellular Rho to stimulate axon growth and regeneration

Ellezam, Benjamin; Dubreuil, Catherine; Winton, Matthew J.; Loy, Leanna; Dergham, Pauline; Belles-Navarro, Inmaculada; McKerracher, Lisa

doi:10.1016/s0079-6123(02)37028-6

Cited by 73 publications

(41 citation statements)

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“…*p Ͻ 0.05. extension, which strictly depend on polymerization and organization of actin filaments (Dickson, 2001;Etienne-Manneville and Hall, 2002;Luo, 2000Luo, , 2002Huber et al, 2003). There is a broad consensus that small GTPase RhoA is central to secondary signaling induced by almost all CNS inhibitors of axon regeneration (Jin and Strittmatter, 1997;Kuhn et al, 1999;Lehmann et al, 1999;Joester and Faissner, 2001;Vinson et al, 2001;Ellezam et al, 2002;Monnier et al, 2003). Activation of RhoA prevents growth cone extension and it stimulates actinomyosin contractility and stress fiber formation via activation of ROCK (Dickson, 2001;Luo, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Activation of RhoA prevents growth cone extension and it stimulates actinomyosin contractility and stress fiber formation via activation of ROCK (Dickson, 2001;Luo, 2002). Furthermore, several studies showed that either pharmacologic or genetic approaches inhibiting activation of RhoA or ROCK completely reverse CNS myelinmediated inhibition in neurite outgrowth assays, and the pharmacologic inhibitors of RhoA and ROCK have also enhanced axonal regeneration, albeit marginally, in spinal cord injury models (Jin and Strittmatter, 1997;Kuhn et al, 1999;Lehmann et al, 1999;Vinson et al, 2001;Dergham et al, 2002;Ellezam et al, 2002;Winton et al, 2002;Fournier et al, 2003). Two previous studies, in the context of MAG, which also showed that the inhibition of neurite outgrowth through the gangliosides is via activation of RhoA and ROCK (Vinson et al, 2001;Yamashita et al, 2002;Mehta et al, 2007), support our findings.…”

Section: Discussionmentioning

confidence: 99%

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Anti-Ganglioside Antibody-Mediated Activation of RhoA Induces Inhibition of Neurite Outgrowth

Zhang¹,

Lehmann

Manoharan

et al. 2011

J. Neurosci.

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Anti-ganglioside antibodies (Abs) are strongly associated with axonal forms of Guillain Barré syndrome (GBS). Some studies indicate that these Abs, including those with GD1a reactivity, are associated with poor prognosis and/or incomplete recovery. We recently demonstrated that a disease-relevant anti-ganglioside Ab with GD1a reactivity inhibits axon regeneration after PNS injury in an animal model (Lehmann et al., 2007). An implication of these findings is that anti-GD1a Abs can mediate inhibition of axon regeneration and limit recovery in some patients with GBS. The downstream inhibitory intracellular signaling that mediates anti-ganglioside Ab-induced axon inhibition remains unclear. In the current study, we show that disease-relevant and GBS patient's anti-ganglioside Abs can inhibit neurite outgrowth in dissociated primary neuronal cultures. Activation of small GTPase RhoA and its key downstream effector Rho kinase (ROCK) are critical mediators of growth cone and neurite outgrowth inhibition. Therefore, we examined the role of these intracellular signaling molecules in our primary neuronal cultures by molecular and pharmacologic approaches. Our results show that the Ab-mediated inhibition of neurite outgrowth involves the activation of RhoA and ROCK pathway and this activation is through the engagement of specific cell-surface gangliosides by Abs. In summary, these studies directly link patient autoantibodies to an intracellular inhibitory signaling pathway involved in anti-ganglioside Abmediated inhibition of neurite outgrowth.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Anti-Ganglioside Antibody-Mediated Activation of RhoA Induces Inhibition of Neurite Outgrowth

Zhang¹,

Lehmann

Manoharan

et al. 2011

J. Neurosci.

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“…ROCK has previously been shown to be inactivated during neurite outgrowth. Therefore, targeting the RhoA/ ROCK signaling pathway is thought to be an attractive strategy for promoting axonal regeneration [8][9][10][11] . Pharmacological inhibition of RhoA with C3 transferase or inhibition of ROCK with Y27632 has been shown to stimulate neurite growth on inhibitory substrates in vitro.…”

Section: Introductionmentioning

confidence: 99%

Expression of a dominant-negative Rho-kinase promotes neurite outgrowth in a microenvironment mimicking injured central nervous system

2010

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Aim: To investigate whether lentiviral vector (LV)-mediated expression of a dominant negative mutant Rho-kinase (DNROCK) could inhibit activation of the Rho/ROCK signaling pathway and promote neurite outgrowth in a hostile microenvironment mimicking the injured central nervous system (CNS) in vitro. Methods: Lentiviral stock was produced using the three-plasmid system by transfecting HEK293 cells. Myelin prepared from rat brain was purified by two rounds of discontinuous density gradient centrifugation and osmotic disintegration. Differentiated PC12 cells and dissociated adult rat dorsal root ganglion (DRG) neurons were transduced with either LV/DNROCK or LV/green fluorescent protein (GFP) and seeded on solubilized myelin proteins. The effect of DNROCK on growth cone morphology was tested by rhodamine-conjugated phalloidin staining. Expression of DNROCK was determined by immunoblotting. The length of the longest neurite, the percentage of neurite-bearing neurons, or the total process outgrowth for all transduced neurons were measured by using the Scion image analysis program.

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“…Rho activation has been shown to correlate with spinal cord injury in a number of studies (Dubreuil et al, 2006;Madura et al, 2004). Inhibition of Rho after neuronal injury encourages axonal outgrowth and regeneration of affected neurons (Ellezam et al, 2002;Madura et al, 2007). Cisplatin and methotrexate clearly retarded the normal development of neurite maturation in both hippocampal and dorsal horn/dorsal root ganglion neurons.…”

Section: Discussionmentioning

confidence: 99%

Anti-cancer drug induced neurotoxicity and identification of Rho pathway signaling modulators as potential neuroprotectants

et al. 2008

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Many chemotherapy drugs are known to cause significant clinical neurotoxicity, which can result in the early cessation of treatment. To identify and develop more effective means of neuroprotection it is important to understand the toxicity of these drugs at the molecular and cellular levels. In the present study, we examine the effects of paclitaxel (taxol), cisplatin, and methotrexate on primary rat neurons including hippocampal, cortical, and dorsal horn/dorsal root ganglion neuronal cultures. We found that all of these anti-cancer drugs induce substantial neurotoxicity evidenced by neurite degeneration. The neurons are capable of recovering after treatment withdrawal, but taxol exerts a biphasic effect that results in the collapse of processes days after treatment is withdrawn. After cisplatin and methotrexate treatment, we observed the degeneration of neuronal processes including the reduction of dendritic branching, length, and altered growth cone formation, indicating an abnormal arrangement of the actin cytoskeleton consistent with the involvement of Rho family small GTPases. Inhibiting RhoA downstream effector p160 ROCK /Rho kinase using Y-27632, or activating p75 neurotrophin receptor (p75 NTR ) using non-peptide mimetic LM11A-31, were able to reverse the degeneration caused by cisplatin and methotrexate. Therefore, the neurotoxicity resulting from exposure to the anti-cancer drugs cisplatin and methotrexate can be alleviated by inhibiting Rho signaling pathway.

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Chapter 26 Inactivation of intracellular Rho to stimulate axon growth and regeneration

Cited by 73 publications

References 50 publications

Anti-Ganglioside Antibody-Mediated Activation of RhoA Induces Inhibition of Neurite Outgrowth

Anti-Ganglioside Antibody-Mediated Activation of RhoA Induces Inhibition of Neurite Outgrowth

Expression of a dominant-negative Rho-kinase promotes neurite outgrowth in a microenvironment mimicking injured central nervous system

Anti-cancer drug induced neurotoxicity and identification of Rho pathway signaling modulators as potential neuroprotectants

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