Neddylation plays a critical role for formation, maturation and maintenance of Schwann cell myelin sheaths.
CIC bioGUNE (Derio/Vizcaya)
Myelinating Schwann cells play a critical role for neuronal function and health. Defective myelination is responsible for the morbidity of a number of peripheral neuropathies, including Charcot-Marie-Tooth disease and diabetic neuropathy. Decades of research has uncovered a complex transcriptional and post-transcriptional program that co-ordinate the formation and maintenance of the myelin sheath. In contrast, much less is known about the functional role of post-translational modification (PTM) of proteins in this remarkable biogenic process.
Neddylation, a PTM that involves the conjugation of the ubiquitin-like protein Nedd8 to protein targets, has recently emerged as a central and versatile regulator of many cellular processes, including ubiquitination, protein transcription and signalling transduction. In Schwann cells, a functional role for neddylation has so far not been defined.
In this study, using various models of genetic and pharmacological inhibition of neddylation in vivo, we show that this PTM has complex and extensive regulatory functions in Schwann cells. For instance, genetic inactivation of NAE1, the enzyme that catalyses neddylation reactions, specifically in developing Schwann cells, leads to striking nerve defects that exhibit all the hallmarks of a severe neuropathy, including gait abnormalities, muscle weakness, and hindlimb clasping. Strikingly, NAE1-deficient mice lack peripheral myelin and exhibit active myelin breakdown of the few formed myelin sheaths. Mechanistically, this severe block of myelination is due to a deficiency in the ubiquitin-mediated degradation of negative regulators of myelination in perinatal nerves, which remain artificially elevated, thus blocking myelination. Notably, we also found an important function of neddylation in maturation and maintenance of myelin sheaths, and in the Schwann cell responses to nerve injury.
In summary, our study reveals that PTMs can play a central role in nerve development, and identifies neddylation as a tractable target for the development of new therapies in demyelinating disorders and for nerve regeneration.
Host: Vicky Sanchez