Oligodendroglial Primary Cilia in White Matter Injury Repair: Function, Signaling mechanism, and Proteome Repertoire

In human CNS white matter injury (WMI) diseases such as multiple sclerosis (MS) in adults and neonatal brain injury that leads to cerebral palsy (CP), remyelination often fails due to insufficient recruitment of oligodendrocyte precursor cells (OPCs) to injury sites.

Understanding the mechanisms that regulate OPCs during remyelination could elucidate the reasons behind the failure of myelin repair in humans.

OPCs consistently produce primary cilia, specialized organelles composed of microtubules that mediate intercellular and intracellular signals.

The role of primary cilia in regulating OPC function and the signaling pathways involved, both during development and remyelination in WMI, remains poorly understood. We aim to demonstrate the role of primary cilia in OPC development and in response to WMI repair.

Mechanistically, we will define the signaling axis starting at the primary cilium as a vital regulator of OPC function, employing a novel technique called cilia-APEX to characterize the proteins localized to OPC primary cilia.

We will validate the identified molecules in human OPC primary cilia in lesioned brain regions to help understand why remyelination is more challenging in humans than in rodents.

Collectively, these studies will highlight that primary cilia play a crucial role as a signaling hub in OPCs for remyelination post-WMI and will uncover potential therapeutic targets for diseases like MS and CP, where the OPC response to injury might be compromised.