The neddylation pathway regulates cytoskeletal dynamics in early neuronal stages

RAQUEL BECERRA; ANNETTE M. VOGL; SEBASTIAN A. GIUSTI; BORDENAVE, MARTÍN D.; CLAUDIA A. VERCELLI; STEFANI, FERNANDO D.; DAMIAN REFOJO

Mar del Plata

Congreso; XXXII Congreso Anual SAN 2017; 2017

Sociedad Argentina de Investigación en Neurociencias (SAN)

Neuronal development is controlled by signalling cascades tightly controlled a myriad of posttranslational modifications. The role of ubiquitin has been well established but the function of the family of ubiquitin-like proteins remains poorly understood.Nedd8 is the UBL with the highest homology to Ub and we recently demonstrated that is highly abundant in the brain and is critical for synapse formation and maintenance. Blocking Nedd8 conjugation with genetic and pharmacological tools reduced axonal and dendritic growth both in cell culture systems and in utero electroporation approaches. These effects were partially reverted by Cytochalasin D, and low doses of Taxol. These results suggest that cytoskeleton dynamics is involved in the effects of Nedd8 on axodendritic growth.To identify the structural details underlying the effects of Nedd8 we employedsuperresolution and fluorescent microscopy. Neddylation blockade with thepharmacological inhibitor MLN4924 strongly reduced microtubular polymerization, induce ectopic lamellipodia formation and increase the growth cone size in early neurons. Finally, in biochemical screenings, we identified several neddylated targets related to the cytoskeleton structure and function. The potential effects of neddylation on some of these specific targets will be discussed