Novel molecular mechanisms underlying anti-ganglioside antibodies-mediated inhibition of axon regeneration

BACAGLIO, CRISTIAN; LOPEZ, PABLO HECTOR HORACIO; ROZÉS SALVADOR, VICTORIA; SCHNAAR, RONALD L.; BÁEZ, BÁRBARA BEATRIZ; CASTAÑARES, CLARA NICOLE

Buenos Aires

Simposio; 3rd Argentinian symposium of glycobiology; 2019

GlycoAr

Anti-ganglioside antibodies (anti-Gg Abs) are associated with poor clinical recovery in Guillain Barrè Syndrome (GBS). It has been demonstrated that anti-Gg Abs produces inhibition of neurite outgrowth by a mechanism that involves the activation of the small GTPase RhoA. At present, the molecular mechanisms underlying RhoA activation are poorly understood, in particular, the identities of ganglioside transducers leading its activation. Based on a recent published proteomic study searching for ganglioside-interacting proteins at neuronal membranes, our lab initiated the screening of signaling molecules related to the inhibitory role of anti-Gg Abs on nerve regeneration. By using an shRNA-based strategy, we initially identified tumor necrosis factor receptor 1A (TNFr1A) as a transducer molecule for the inhibitory effect of anti-GD1a mAb but not anti-GT1b specific mAb on Dorsal Root Ganglion neurons (DRGn), showing specificity on the interaction. These results were confirmed using DRGn cultures from TNFr1A-null mice and the use of an in vivo model of axon regeneration. Interestingly, lack of TNFr1A expression in DRGn abolished the ability of anti-GD1a mAb to activate RhoA. We also identified the pertussis toxin-sensitive guanine nucleotide-binding protein G(i) subunit α-2 as part of the signaling cascade triggered by anti-Gg Abs. Altogether these novel findings represent a step forward towards understanding the molecular mechanisms underlying impaired recovery in GBS.