Title : Neddylation is Essential for Oligodendrocyte Differentiation and Myelination Process
Abstract:
The myelin sheaths that cover the axons are essential for the conduction of nerve impulses in the nervous system. In this regard, mature oligodendrocytes are the myelinating cells of the central nervous system (CNS). In recent decades, research on the mechanisms involved in myelination has generally focused on transcriptional ones, whereas post-translational ones remain mainly unknown. In this line, neddylation, an ubiquitylation-like pathway that conjugates an ubiquitin-like protein NEDD8 to target proteins, has emerged as a critical regulatory process controlling ubiquitination, protein transcription and signalling transduction. Dysregulation of neddylation has been recently linked to CNS pathological conditions, including epilepsy and multiple sclerosis. On this basis, our aim is to study the role of neddylation in oligodendrocytes and, consequently, in myelination. For this purpose, we used MLN4924 (Pevonedistat), an FDA- and EU-designated Orphan Drug, an inhibitor that acts on NAE, the initiating enzyme in the neddylation cascade. First, we studied its effect during development, by injecting MLN intraperitoneally into rats from postnatal day 7 to 15. In the brain and spinal cord of these rats, there was a significant impairment of the expression of proteins present in the membrane of myelinating oligodendrocytes, such as MBP and MAG. Likewise, in MLN-treated cortical oligodendrocyte cultures, the inhibition of neddylation caused a significant decrease in cell viability and the expression of MBP and MAG, among others. Together, these results indicate that neddylation inhibition compromises both the viability and the level of differentiation and maturation of oligodendrocytes, and may negatively affect the formation and maintenance of myelin sheaths in the CNS. These findings shed light on the post-translational mechanisms involved in myelination and lay the groundwork for future studies on the role of neddylation in degenerative diseases.
What will audience learn from your presentation?
- Neddylation is essential for not only neural development but also for glial development.
- Its disruption leads to different neurodenerative diseases
- Neddylation can be involved in different pathological conditions discussed in the conference
- It can be pharmacologically and genetically inhibited, affording a good tool for its study.
