Neddylation is a global orchestrator of the molecular network driving Schwann cell myelination

Axonal myelination is essential for neuronal function and health. In peripheral nerves, deficient myelination is responsible for the morbidity of various forms of inherited or acquired neuropathies, including Charcot-Marie-Tooth disease and diabetic neuropathy. Decades of research have uncovered a complex transcriptional and post-transcriptional program that co-ordinates 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 gene transcription, metabolism, and cellular differentiation. In this study, we show that genetic and pharmacological inhibition of neddylation in vivo in developing Schwann cells lead to striking nerve defects that exhibit the classical hallmarks of a severe neuropathy, including gait abnormalities, muscle weakness, and hindlimb clasping, ultimately leading to early death. The mutant mice lack peripheral myelin and develop secondary axonal loss, and we demonstrate, at the mechanistic level, that neddylation regulates multiple critical myelination-related pathways. Together, our findings identify neddylation as a central regulatory hub of control of peripheral myelination and delineate the potential pathogenetic mechanisms in inherited human PNS disorders, characterized by mutations in genes related to the neddylation pathway.

轴突髓鞘形成（Axonal myelination）对神经元的功能与健康至关重要。在周围神经中，髓鞘形成缺陷是多种遗传性或获得性神经病（包括夏科-马里-图思病（Charcot-Marie-Tooth disease）与糖尿病性神经病）发病的核心诱因。数十年的研究已揭示了一套复杂的转录及转录后调控程序，可协调髓鞘的形成与维持。与之形成鲜明对比的是，人们对蛋白质翻译后修饰（post-translational modification, PTM）在这一精妙的生物发生过程中发挥的功能作用仍所知甚少。

Neddylation修饰（Neddylation）是一类将泛素样蛋白Nedd8结合至蛋白质靶标的翻译后修饰，近年来其已被证实是众多细胞过程（包括基因转录、代谢及细胞分化）的核心且多效调控因子。本研究中，我们证实：在发育中的施万细胞（Schwann cells）体内对Neddylation进行遗传与药理学抑制，会引发显著的神经缺陷，这些缺陷表现为严重神经病的典型特征，包括步态异常、肌肉无力及后肢蜷缩抱持，最终导致受试小鼠早期死亡。该突变小鼠缺乏周围神经髓鞘，并会发生继发性轴突丢失；我们还从机制层面证实，Neddylation可调控多条关键的髓鞘形成相关通路。

综上，我们的研究结果证实Neddylation是调控周围髓鞘形成的核心调控枢纽，并阐明了以Neddylation通路相关基因突变为特征的人类遗传性周围神经系统（Peripheral Nervous System, PNS）疾病的潜在致病机制。