Guillain Barré Syndrome-associated anti-glycan antibodies halt axon regeneration by inhibiting microtubule assembly via RhoA-ROCK dependent inactivation of CRMP-2.

ROZÉS SALVADOR, V.; HEREDIA, F.; WOJNACKI, J. ; PALANDRI, A. ; CACERES, A; LOPEZ, P.H.H.

Mar del Plata

Congreso; XXX Annual Meeting de la Sociedad Argentina de Investigación en Neurociencias.; 2015

Axon regeneration is a response of injured nerve cells critical for the nerve repair in human acute immune neuropathies such as Guillain Barrè Syndrome (GBS). Clinical studies associate the presence of anti-ganglioside antibodies (anti-Gg abs) with poor recovery in GBS. Passive transfer of mAb (GD1a/GT1b, clone 1B7) in an animal model halts axon regeneration. Cultures of dissociated DRG neurons (DRGn) demonstrated that anti-Gs inhibits neurite outgrowth via activation of RhoA/ROCK-dependent pathways. The aim of this work is to study the molecular basis of the inhibitory anti-Gg abs-effect on neurite outgrowth. Time-lapse video microscopy was used to study their dynamics at growth cones (GC) in DRGn cultures together with immunofluorescence analysis of stable/dynamic microtubules (MT). Studies of 1B7-triggered signaling events included activity of small GTPase RhoA and its downstream target Collapsin response mediator protein-2 (CRMP-2). 1B7-treated DRGn cultures display reorganization of cytoskeleton´s components such as a rapid loss of filopodia and collapse of lamella followed by a delayed in MT retraction. MT but not lamella alterations were preceded by increase in RhoA activity. Y-27632 and C3 treatment did not reverse alterations in lamella. Electroporation of animals with a mutant CRMP-2 T-555A overcome 1B7-induce axon regeneration inhibition. Our results suggest that anti-Gg abs induce halt in axon regeneration by RhoA/ROCK-dependent and independent signaling pathways.