Anti-glycan antibodies halt axon regeneration in a model of Guillain Barrè Syndrome axonal neuropathy by inducing microtubule disorganization via RhoA-ROCK-dependent inactivation of CRMP-2

Victoria Rozés Salvador, Florencia Heredia, Andrés Berardo, Anabela Palandri, Jose Wojnacki, Ana L. Vivinetto, Kazim A. Sheikh, Alfredo Caceres, Pablo H.H. Lopez

Research output: Contribution to journalArticle

Abstract

Several reports have linked the presence of high titers of anti-Gg Abs with delayed recovery/poor prognosis in GBS. In most cases, failure to recover is associated with halted/deficient axon regeneration. Previous work identified that monoclonal and patient-derived anti-Gg Abs can act as inhibitory factors in an animal model of axon regeneration. Further studies using primary dorsal root ganglion neuron (DRGn) cultures demonstrated that anti-Gg Abs can inhibit neurite outgrowth by targeting gangliosides via activation of the small GTPase RhoA and its associated kinase (ROCK), a signaling pathway common to other established inhibitors of axon regeneration. We aimed to study the molecular basis of the inhibitory effect of anti-Gg abs on neurite outgrowth by dissecting the molecular dynamics of growth cones (GC) cytoskeleton in relation to the spatial-temporal analysis of RhoA activity. We now report that axon growth inhibition in DRGn induced by a well characterized mAb targeting gangliosides GD1a/GT1b involves: i) an early RhoA/ROCK-independent collapse of lamellipodia; ii) a RhoA/ROCK-dependent shrinking of filopodia; and iii) alteration of GC microtubule organization/and presumably dynamics via RhoA/ROCK-dependent phosphorylation of CRMP-2 at threonine 555. Our results also show that mAb 1B7 inhibits peripheral axon regeneration in an animal model via phosphorylation/inactivation of CRMP-2 at threonine 555. Overall, our data may help to explain the molecular mechanisms underlying impaired nerve repair in GBS. Future work should define RhoA-independent pathway/s and effectors regulating actin cytoskeleton, thus providing an opportunity for the design of a successful therapy to guarantee an efficient target reinnervation.

Original languageEnglish (US)
Pages (from-to)42-53
Number of pages12
JournalExperimental Neurology
Volume278
DOIs
StatePublished - Apr 1 2016
Externally publishedYes

Keywords

  • Anti-glycan antibodies
  • Axon regeneration
  • Ganglioside
  • Guillain Barrè Syndrome
  • Nerve repair
  • Peripheral nerve
  • RhoA GTPase

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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