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

ROZÉS SALVADOR V; HEREDIA F; BERARDO A; PALANDRI A; WOJNAKI J; VIVINETTO A; KAZIM S; CACERES A; LOPEZ P H H

EXPERIMENTAL NEUROLOGY

ACADEMIC PRESS INC ELSEVIER SCIENCE

Lugar: Amsterdan; Año: 2016 p. 42 - 53

0014-4886

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 thatmonoclonal and patient-derived anti-Gg Abs can act as inhibitory factors in an animalmodel of axon regeneration.Further studies using primary dorsal root ganglion neuron (DRGn) cultures demonstrated that anti-Gg Abs can inhibitneurite 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 themolecular basis of the inhibitory effect of anti-Gg abs on neurite outgrowth by dissecting the molecular dynamics ofgrowth cones (GC) cytoskeleton in relation to the spatial?temporal analysis of RhoA activity.We now report thataxon 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 GCmicrotubule organization/and presumably dynamics via RhoA/ROCK-dependent phosphorylationof CRMP-2 at threonine 555. Our results also showthat mAb 1B7 inhibits peripheral axon regeneration in ananimal model via phosphorylation/inactivation of CRMP-2 at threonine 555. Overall, our data may help to explainthemolecularmechanisms underlying impaired nerve repair in GBS. Future work should define RhoA-independentpathway/s and effectors regulating actin cytoskeleton, thus providing an opportunity for the design of a successfultherapy to guarantee an efficient target reinnervation.