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. 2011 Jul 1;2(4):233–238. doi: 10.4161/sgtp.2.4.17115

Autoantobodies activate small GTPase RhoA to modulate neurite outgrowth

Kazim A Sheikh 1,✉
PMCID: PMC3225914  PMID: 22145097

Abstract

This review illustrates an example of adaptive immune responses (auto-antibodies) modulating growth/repair behavior of neurons in the disease context of Guillain-Barré syndrome (GBS), which is a prototypic autoimmune, acute monophasic disorder of the peripheral nerves that is the commonest cause of acute flaccid paralysis worldwide. Anti-ganglioside antibodies (Abs) are the most commonly recognized autoimmune markers in all forms of GBS and these Abs are associated with poor recovery. Extent of axonal injury and failure of axonal regeneration are critical determinants of recovery after GBS. In this clinical context, our group examined the hypothesis that anti-ganglioside Abs adversely affect axon regeneration after peripheral nerve injury. We show that anti-ganglioside Abs inhibit axon regeneration in preclinical cell culture and animal models. This inhibition is mediated by activation of small GTPase RhoA and its downstream effector Rho kinase (ROCK) by modulation of growth cone extension and associated neurite elongation in neuronal cultures. Our studies suggest that RhoA and ROCK are potential targets for development of novel therapeutic strategies to enhance nerve repair.

Key words: Guillain-Barré syndrome, anti-ganglioside antibodies, RhoA, axon regeneration, neurite outgrowth, nerve repair

Small GTPases of the Rho family, including RhoA, Rac1 and Cdc42, are known regulators of growth cone motility in neurons. RhoA is implicated as major negative regulator of growth cone extension in several experimental paradigms examining effects of inhibitory environmental cues on growth cone extension. Our group is examining the pathobiologic effects of autoAbs directed against glycan antigens carried by specific gangliosides (sialic-acid containing glycolipids) enriched in neuronal cells. These autoAbs against gangliosides have been reported in several neuroimmunological disorders but they have strongest association with certain variants of Guillain-Barré syndrome (GBS). It is in this disease context we have examined the pathobiologic effects of these autoAbs on nerve repair in animal and cell culture models showing that specific anti-ganglioside Abs inhibit axon regeneration and this inhibition is mediated through RhoA and its downstream signaling partners.

GBS

With the near-eradication of polio, GBS has become the most frequent cause of acute flaccid paralysis. The worldwide incidence of this disease is 1–1.5/100,000 population. Affected persons rapidly develop weakness of the limbs and often of the respiratory muscles and lose deep tendon reflexes. Despite two beneficial treatments, plasmapheresis and intravenous immunoglobulin, GBS remains a major public health burden. Most affected individuals have an uneventful recovery, but a significant proportion of patients require mechanical ventilation and 20–30% have severe and permanent neurologic sequelae, including 10–20% who cannot walk unaided.1–3 The prevalence and health costs of post-GBS cases with residual deficits are not known. Patients with residual deficits and significant disability almost always have axonal injury and target denervation; recovery thus requires regeneration from the site of axonal transection. Although the adult mammalian peripheral nervous system (PNS) readily regenerates after injury, the mechanisms underlying failure of axon regeneration in GBS cases with permanent neurologic sequelae are not clear.

It is now widely accepted that there are two major forms of GBS, demyelinating and axonal. In developed countries including US, Europe and Australia, the pathophysiologic process in the predominant form of GBS is demyelination and termed Acute Inflammatory Demyelinating Polyneuropathy (AIDP).2,3 In China, a form, acute motor axonal neuropathy (AMAN), in which the primary pathophysiological process involves disruption of motor axonal function, not demyelination was identified.4 Severe axonal cases also have sensory nerve fiber involvement and are called acute motor sensory axonal neuropathy (AMSAN). Minor forms of GBS include Fisher, sensory-ataxic and other variants.5,6 The demyelinating and axonal forms are distinguished by electrodiagnostic testing, whereas minor forms are recognized by constellation of clinical features and disease course.

GBS and Anti-Ganglioside Abs

Anti-ganglioside Abs are the most commonly recognized autoimmune markers in all forms of GBS, therefore, there is considerable interest in defining the spectrum of their pathobiologic effects and associated mechanisms. Two major—GM1 and GD1a, and two minor—GalNAc-GD1a and GM1b, gangliosides are implicated as target antigens in AMAN form of GBS. Abs against GM1 and GD1a gangliosides can be detected in up to 50 to 60% of AMAN patients in Japanese and northern Chinese populations, respectively. The frequency of anti-GalNAc-GD1a and GM1b Abs in motor predominant syndromes is much lower (10–15%). Anti-GQ1b Abs occur in 80–90% of patients with Fisher syndrome (FS) providing the strongest association between Abs to a specific ganglioside and a clinical phenotype.2,3,5,6 Anti-ganglioside Abs with various specificities (mostly GM1) also occur in up to 30% of patients with AIDP.7 Recent studies have indicated that a proportion of patients with FS and AMAN form of GBS who were seronegative when tested against individual gangliosides in solid phase assays become seropositive when tested with mixture of two different gangliosides. These novel observations raise the possibility that number of seronegative patients in GBS, particularly AIDP variant, could decrease as sera from these patients are tested against mixture of gangliosides/glycolipids.

Work over the past 20 years has led to the hypothesis of post-infectious molecular mimicry as the predominant pathophysiologic mechanism for generation of anti-ganglioside Abs and axonal and FS forms of the disease,3,5,6,8,9 supported by the following key observations: (1) C. jejuni enteritis is the most commonly recognized antecedent infection in GBS;3 (2) different variants of GBS, particularly FS and AMAN, are strongly associated with specific anti-ganglioside Abs;2,3,5,6 (3) the lipooligosaccharides of C. jejuni isolates from patients with GBS carry relevant ganglioside-like moieties and relevant enzymatic machinery to synthesize these glycans;10–13 (4) gangliosides, the purported target antigens, are enriched in nerve fibers;14,15 (5) pathological and immunopathological studies in the AMAN indicate antibody (Ab)-mediated axonal injury;16 and (6) experimental studies showing pathogenicity of anti-ganglioside Abs to produce dysfunction or disruption of intact nerve fibers in preclinical models of AMAN and FS.8,17,18

Nerve repair/regeneration forms the basis of recovery in the majority of patients with GBS. Our group has focused on the pathophysiologic effects of anti-ganglioside Abs on nerve repair/regeneration (injured nerve fibers) for last few years keeping in view the patients with incomplete recovery and the following related clinical observations. Several studies have suggested that GBS patients with IgG and/or IgM anti-ganglioside Abs directed against GM1 or GD1a or ganglioside complexes are more likely to recover slowly and have poor prognosis (reviewed in ref. 9 and 19). Further, Press et al. reported that anti-GM1 IgG and anti-GD1a Abs peak in the serum after the acute phase of GBS, suggesting that these Abs are produced secondary to nerve damage in GBS. These authors hypothesize that their data do “not exclude the possibility that secondarily induced anti-GM1 and -GD1a Abs may themselves be biologically active and play a role in disease propagation and/or recovery from disease in some patients with GBS.”20 The poor recovery is not restricted to axonal forms but is also seen in AIDP. Poor recovery is known to reflect failure of axon regeneration and reinnervation of targets in all forms of GBS (reviewed in ref. 19), therefore, we examined the effects of anti-ganglioside (anti-GD1a and anti-GM1) Abs on nerve repair particularly on axon regeneration in animal and cell culture models.

Gangliosides

Gangliosides, the target antigens of anti-ganglioside Abs, are major cell surface determinants and the predominant sialo-glycoconjugates in the mammalian nervous system. They contain one or more sialic acids linked to an oligosaccharide chain, of variable length and complexity, which is attached to ceramide lipid anchor. The ganglio series subfamily of gangliosides predominates in the mammalian nervous system. Ganglioside structures are more complex in the nervous system as compared with other organs such as liver, implying specific nervous system biological functions.21 They are biosynthesized by sequential action of specific glycosyltransferases. The charged sialic acid-containing carbohydrate core projects from the cell surface, while the nonpolar ceramide portion anchors these moieties into the plasma membrane, and anti-ganglioside Abs bind to these carbohydrate moieties. Multiple studies indicate that gangliosides are concentrated in microdomains called lipid rafts that are specialized for cell signaling (see below).

The most abundant gangliosides in the adult mammalian nervous system, GM1, GD1a, GD1b and GT1b, are closely related and contain a ceramide lipid, a neutral tetrasaccharide core (Gal β3 GalNAc β4 gal β4 Glc), and one or more sialic acids; in peripheral nerves LM1 ganglioside is also enriched, particularly in myelin.22,23 Polysialylated complex gangliosides are more concentrated in the axolemma fractions; GM1 is enriched in both axons and myelin. Experimental studies indicate that nerve injury induces alteration of ganglioside biosynthesis of complex gangliosides and that GD1a and GT1b are the two major gangliosides in regenerating axons, but changes in GM1 expression are not completely characterized.24 This previous work indicates that the injured and regenerating axons express complex gangliosides, which could be targeted by anti-ganglioside Abs.

Growth Cone Motility and Relevant Signaling Molecules

Growth cones sample their environment by extending lamellipodia and filopodia, which strictly depend upon polymerization and organization of actin filaments. Small GTPases of the Rho family, including RhoA, Rac1 and Cdc42, are known regulators of the actin cytoskeleton in all eukaryotic cells.25,26 Generally, these molecules cycle between GTP-bound active and GDP-bound inactive states through the binding of guanine nucleotides. Under resting conditions these proteins are kept inactive by GDI. Rho GTPases are also regulated by enzymes either that catalyze guanine nucleotide (GDP or GTP) exchange by the GTPase (GEFs-GTP-exchange factors) or those that increase GTP hydrolysis (GAPs-GTPase activating proteins). Activated forms of Rho GTPases interact with a series of cytosolic enzymes to reorganize the cytoskeleton by regulating actin filament assembly and disassembly by controlling actin polymerization, branching, and depolymerization and directing actin-myosin-dependent contractility to control the retrograde transport of F actin within the growth cones.25–29 Activation of RhoA stimulates actinomyosin contractility and stress fiber formation, thus inhibiting growth cone extension, whereas activation of Cdc42 and Rac1 is associated with extension of filopodia and lamellopodia, respectively. In general, Rac1 and Cdc42 are positive regulators that promote neurite extension, whereas RhoA is a negative regulator that inhibits neurite outgrowth and/or collapse of growth cones. Several lines of evidence indicate that activation of RhoA is central to inhibition by CNS myelin inhibitors and proteoglycans.27,30 Rho kinase (ROCK), a major RhoA effector, is also involved in reorganization of the growth cone cytoskeleton. Therefore, our studies with anti-ganglioside Abs focused on activation of small GTPase RhoA as a molecular mechanism underlying inhibition of axon regeneration.

Lipid Rafts and Gangliosides as Mediators of Inhibition of Axon Regeneration: Lessons from Central Nervous System (CNS)

The term “lipid raft” has been used to describe cholesterol and sphingolipid-rich liquid-ordered microdomains within cell membranes. Typically, lipid rafts are characterized by insolubility in detergents at 4°C and can be isolated by their buoyancy in sucrose gradients. A range of signaling molecules has been detected in these microdomains, including GPI-linked proteins, T- and B-cell receptors, Src-family tyrosine kinases, G-proteins, growth factor receptors and integrins. Gangliosides have been suggested to mediate diverse biologic effects through organization of the plasma membrane into lipid rafts with unique ganglioside compositions, which then directly affect signaling through different receptors. Recently three models were proposed to explain the mechanisms of receptor regulation by gangliosides: ligand interaction with gangliosides instead of cognate receptors; modulation of receptor dimerization; and modulation of receptor activation state and subcellular localization.31 A complementary model proposes that modulation of glycans, including gangliosides, in lipid rafts can by itself transduce intracellular signaling, a concept termed glycosynapse.32 This model, however, does not explain how the signals from gangliosides in the outer leaflet of plasma membrane are transduced to the inner leaflet of cell membrane where signal-transducing proteins reside.

Signaling through lipid rafts in growth cones is now considered critical to failure of axonal regeneration in response to inhibitory signaling cues after CNS injury. Inhibitory signaling induced by CNS myelin proteins is well characterized and Nogo receptor (NgR1) is central to this inhibition. NgR1 is a GPI-linked glycoprotein contained in the lipid rafts which requires transmembrane co-receptors for intracellular signal transduction across the plasma membrane. p75 and TROY (TNFR family members) have been shown to act as signaling partners for NgR and to activate the small GTPase RhoA signaling cascade, which then orchestrates inhibition of growth cone extension. Moreover, multiple studies indicate that myelin-associated glycoprotein (MAG), a CNS myelin protein, can induce inhibition of neurite outgrowth via two independent sets of signaling complexes in lipid rafts: (a) NgR and TNFR (p75 or TROY) complex;29 and (b) gangliosides GD1a and/or GT1b33 and TNFR (p75) complex.34

In the injured CNS, myelin proteins activate RhoA through TNFRs.35 How do TNFRs mediate RhoA activation? This has been examined in the context of p75. Overexpression of p75 is sufficient to activate endogenous RhoA in both neuronal and non-neuronal cells. Yamashita et al. detected an interaction between p75 and RhoA by a yeast two-hybrid screen, but direct interaction in neuronal cells was not found.36 These authors then proposed that CNS myelin inhibitors strengthen p75 binding to Rho-guanine dissociation inhibitor (GDI), which normally sequesters RhoA in cytoplasm and prevents its activation, and this binding prevents Rho-GDI from inhibiting RhoA, thereby allowing as yet unknown guanine nucleotide exchange factors (GEFs) to activate RhoA.37 Recently, Harrington et al. reported that Kalirin9, a dual Rho-GEF, binds p75 directly and regulates p75-Nogo receptor-dependent RhoA activation and neurite inhibition in response to MAG.38 In this myelin-initiated signaling cascade, RhoA activation leads to reorganization of growth cone cytoskeleton via activation of ROCK.39 Based on the work reviewed above we hypothesized that crosslinking gangliosides in lipid rafts transduce intracellular signaling via an adaptor protein such as p75 and tested this hypothesis in p75 null mice (see below).

Anti-Ganglioside Ab-Mediated Inhibition of Axon Regeneration

We have examined Ab-mediated inhibition of axon regeneration in animal and cell culture models.

Animal studies.

Our initial studies focused on establishing an animal model in which effects of anti-ganglioside Abs on axon regeneration could be examined.40 Nerve crush provides a convenient and well characterized system to study the regeneration of injured axons mimicking the regenerative response of degenerated/transected/injured axons in GBS. We found that passive immunization with disease relevant anti-GD1a reactive Abs induced severe inhibition of axon regeneration in sciatic nerve crush model that prevented reinnervation of targets such as muscles. The morphology of injured axonal tips that failed to regenerate was reminiscent of stalled growth cones called dystrophic bulbs or sprouts, typically seen after CNS injury. The inhibition was dependent on Ab engaging specific axonal surface gangliosides as mice lacking complex gangliosides including GD1a were completely resistant to the inhibitory effects of anti-GD1a reactive Abs used in this study. That Ab-mediated inhibition of axon regeneration was not a result of complement-mediated cytolytic injury was indicated by the results showing that mice deficient in C5 component of complement cascade were susceptible to Ab-mediated inhibition of axon regeneration.40 These studies showed that passive transfer of Abs directed against cell surface glycans severely inhibited regeneration of peripheral nerve axons.

In a subsequent study,19 human sera with anti-GM1 Abs or purified anti-GM1 Abs from patient sera were also tested in sciatic nerve crush model. We found that passive transfer of patient Abs also inhibited axon regeneration in animal model. Patient Abs were compared with cholera toxin B subunit (a high affinity GM1 ligand) and a monoclonal anti-GM1 Ab. Axon regeneration was also inhibited by Cholera toxin B subunit but not by monoclonal anti-GM1 Ab. Further biochemical studies comparing cholera toxin B subunit and patient and monoclonal anti-GM1 Abs indicated that both affinity and fine specificity of GM1 ligands influenced whether or not an individual ligand inhibited axon regeneration.19 These studies directly linked human autoimmune Abs from GBS patients with inhibition of axon regeneration and provide an explanation for poor recovery in some GBS patients with anti-ganglioside Abs. Our data demonstrate that that circulating autoimmune Abs can inhibit axon regeneration through neuronal gangliosides independent of endogenous regeneration inhibitors.

Cell culture studies.

We established neuronal culture models to study inhibitory effects of anti-ganglioside Abs on neurite growth and growth cone behavior.41 Development of cell culture models also allowed us to study the downstream inhibitory intracellular signaling that mediates anti-ganglioside Ab-induced axon inhibition. We found that disease-relevant and GBS patient's anti-ganglioside Abs can inhibit neurite outgrowth in dissociated primary sensory and motor neuron cultures. The Ab-mediated inhibitory effects were seen in embryonic, post-natal and adult neuron cultures. We performed Schwann cell depleted cultures to show that Ab-mediated inhibition is at the level of axon and not due to indirect injury of glial/Schwann cells;41 an issue that could not be addressed in animal studies. That Ab-mediated inhibition was through gangliosides was again confirmed in cell cultures studies as neurons obtained from mutant mice lacking complex gangliosides were not susceptible to antiganglioside Abs.

Abortive sprouting responses in neuronal cultures are frequently accompanied by growth cone collapse. We examined growth cone morphology in anti-ganglioside Ab-treated cultures and observed growth cone simplification, i.e., decreased growth cone area and number of filopodia/growth cone within 30 min of Ab treatment. Ab treatment for 24 h significantly increased the number of collapsed growth cones.41 These observations supported the notion that Ab-mediated inhibition of neurite outgrowth is at least partly mediated at the level of growth cones. This idea was further tested in Xenopus spinal neurons in which localized growth cone collapse leads to repulsive response of growth cones. A gradient of anti-GD1a reactive Abs induced repulsive turning responses of growth cones in this model.41 Overall, cell cultures and growth cone studies showed that anti-ganglioside Abs mimicked the inhibitory effects of CNS myelin proteins on neurons in cultures.

RhoA and ROCK Activation Induce Inhibition of Neurite Outgrowth: Findings and Unresolved Issues

Activation of small GTPase RhoA and its key downstream effector ROCK are critical mediators of growth cone and neurite outgrowth inhibition. Given our cell culture findings, we examined the role of these intracellular signaling molecules in our primary neuronal cultures by genetic/molecular and pharmacologic approaches. Our studies found that the Ab-mediated inhibition of neurite outgrowth is reversed if activation of RhoA and ROCK pathway is prevented. Reversal of inhibition with ROCK inhibitor (Y27632) was almost complete, likely due to small size and cell permeability of this molecule compared with RhoA inhibitor (C3 transferase). Furthermore, activation of RhoA is through the engagement of specific cell-surface gangliosides by Abs because neurons from mice lacking complex gangliosides neither showed changes in RhoA activation and nor modulation of neurite outgrowth. Since gangliosides are confined to the outer leaflet of the plasma membrane we examined the role of p75, a transmembrane adaptor protein implicated in intraneuronal inhibitory signaling induced by CNS myelin proteins. This issue was examined in p75-null mice and our studies showed that p75-null mice are susceptible to anti-ganglioside Ab-mediated inhibition of axon regeneration indicating that p75 is not involved in inhibitory signaling in our animal model.41

Two unresolved issues of critical importance include: (a) whether RhoA and ROCK activation is involved in Ab-mediated inhibition in animal model; and (b) whether a transmembrane adaptor molecule is necessary for Ab-mediated activation of intracellular signaling, if so, then the identity of such molecule(s), and if not, then mechanisms involved in intracellular signaling resulting from perturbation of cell surface glycolipids confined to the outer leaflet of plasma membranes. Our group is in the process of examining these issues.

RhoA as a Therapeutic Target: Opportunity and Challenge

Our studies indicate that RhoA and ROCK in neuronal/axonal compartments of peripheral nerves are potential target molecules for therapeutic intervention(s) to enhance axon regeneration. Modulation of these molecules could enhance axon regeneration not only in anti-ganglioside Ab-mediated immune neuropathies but in other peripheral nerve disorders in which disease processes inhibit axon regeneration via activation of RhoA and ROCK signaling. In order for this strategy to become successful the challenge to overcome is selective modulation of RhoA and ROCK in neuronal/axonal compartments of the nerve but not other cells. RhoA and ROCK are expressed ubiquitously. In peripheral nerves, neurons/axons, Schwann cells and macrophages are critical cellular elements that respond to injury and participate in nerve repair. There is some evidence indicating that RhoA and ROCK activation is involved in macrophage attachment to injured nerve fibers,42 a critical step for the clearance of debris and Schwann cell myelination,43 processes that are necessary for normal nerve repair. Nonselective inhibition of RhoA and ROCK in neuronal and nonneuronal compartments of the nerve may not yield net beneficial effect on repair. We believe development of strategies that allows selective inhibition of RhoA pathway in neuronal/axonal compartment is more likely to enhance axon regeneration and associated nerve repair than nonselective targeting of this pathway. This assertion is partly supported by observations that either pharmacologic or genetic approaches inhibiting activation of RhoA or ROCK completely reverse CNS myelin-mediated inhibition in neurite outgrowth assays, but the nonselective pharmacologic inhibitors of RhoA and ROCK enhanced axonal regeneration, only modestly, in CNS injury animal models.39,44,45 Anti-ganglioside antibodies may involve specific Rho-GEFs in neuronal/axonal compartments to induce activation of RhoA. Further, if the specific Rho-GEFs involved in the inhibitory signaling were restricted to neuronal/axonal compartment then therapeutic targeting of these exchange factors could allow prevention of RhoA activation selectively in neuronal/axonal compartment.

Acknowledgements

Dr. Sheikh is supported by NIH/NINDS (NS42888 and NS54962) and GBS/CIDP Foundation.

Extra View to: Zhang G, Lehmann HC, Manoharan S, Hashmi M, Shim S, Ming GL, et al. Antiganglioside antibody-mediated activation of RhoA induces inhibition of neurite outgrowth. J Neurosci. 2011;31:1664–1675. doi: 10.1523/JNEUROSCI.3829-10.2011.

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