Determining the role of circadian transcriptional control in myelin-forming precursors in neurodegeneration

The causes of neurodegenerative disorders like multiple sclerosis or Alzheimer’s disease are incompletely understood, hindering our ability to gain precise diagnoses and design effective therapeutics. While current models of neurodegeneration focus on changes in neuronal signaling, myelin is integral to neural circuit function. Myelin—the structure surrounding nerves—is necessary for the efficient communication between neurons. The severe clinical symptoms that arise as neurodegenerative disorders progress are exacerbated by the loss of oligodendrocytes—myelin-producing cells—and impair differentiation of oligodendrocyte precursor cells (OPCs).

To understand the processes leading to myelin loss and develop targeted therapies to restore myelination, we need a comprehensive understanding of the mechanisms controlling myelin-forming cells. OPC are the most proliferative cells of the brain and their proliferation cycles over the circadian or 24-hour day. Each cell of the body has a molecular clock that aids in the response to daily fluctuations. Our preliminary data shows that by disrupting the OPC circadian clock their proliferation and remyelination capacity are deficient. My aim is to determine how the circadian clock controls OPC proliferation and differentiation into myelin-forming cells, and to evaluate how its genetic disruption affects neurodegenerative diseases of dysregulated myelination.

I propose to characterize which genes are controlled by the circadian clock in OPCs by studying circadian intact and dysregulated OPCs from mice in which the main clock gene was specifically eliminated from these cells. I will apply molecular techniques to sequence the DNA and measure gene expression to establish which are the genes controlled in OPCs by the circadian clock. This will enable us to precisely determine the pathways controlled by circadian rhythms in myelin-forming cells. Understanding how the circadian rhythms regulate myelin-forming precursors will impart unique insights into normal and aberrant myelination and will have a positive impact on developing therapeutic strategies to restructure myelin.