Periodic Reporting for period 4 - Myel-IN-Crisis (Myelin at the crossroads of Development and Disease)
Période du rapport: 2023-04-01 au 2025-03-31
The oligodendrocyte, by far the largest cell in mammalian biology, greatly enables central nervous system (CNS) function through prolific production of a single substance: myelin. Oligodendrocytes undergo a dramatic metamorphosis during myelination, increasing their cell surface area ~6500-fold with proteolipid extensions to nerve axons in the CNS white matter. How is this synthetic feat accomplished? We lack a comprehensive understanding of machinery that precisely coordinates transcription, translation, lipid synthesis and energy production. Moreover, how do these mechanisms become so intensively upregulated during myelination? Does this extraordinary transient state put the myelinating oligodendrocyte at risk of death in diseases of white matter? These questions underlie the Aims of the proposal “Myel-IN-crisis.”
Since 2018, the project has advanced understanding of oligodendrocyte biology and myelination resulting in 8 publications (several more in preparation).
We established key methodological platforms to test an Integrated Synthetic Programme (ISP) controlling oligodendrocyte differentiation, metabolism, and myelination (Aim 1). This includes optimized OPC culture systems, RNA-Seq studies revealing heightened iron metabolism requirements under HIF pathway modulation, proteomic profiling, and development of the LaST map high-resolution spatial transcriptomics pipeline (Nat Neurosci, 2020).
We have identified a novel mechanism for nuclear transport of mRNA in microglia, which provides insight into the pathology of multiple sclerosis.
Aim 4 delivered major insights into multiple sclerosis (MS) pathobiology (Schirmer et al Nature 2019 PMID: 31316211), identifying selectively vulnerable upper cortical layer neurons and a novel phagocyte signature from cells ingesting myelin mRNA.
We established key methodological platforms to test an Integrated Synthetic Programme (ISP) controlling oligodendrocyte differentiation, metabolism, and myelination (Aim 1). This includes optimized OPC culture systems, RNA-Seq studies revealing heightened iron metabolism requirements under HIF pathway modulation, proteomic profiling, and development of the LaST map high-resolution spatial transcriptomics pipeline (Nat Neurosci, 2020).
We have identified a novel mechanism for nuclear transport of mRNA in microglia, which provides insight into the pathology of multiple sclerosis.
Aim 4 delivered major insights into multiple sclerosis (MS) pathobiology (Schirmer et al Nature 2019 PMID: 31316211), identifying selectively vulnerable upper cortical layer neurons and a novel phagocyte signature from cells ingesting myelin mRNA.
Follow-up work has examined neuronal vulnerability mechanisms, mRNA trafficking into microglia, microglia–tumor/fetal brain interactions (Bulstrode et al Neuron 2022 PMID: 36174572), and oligodendrocyte roles in neurodegenerative disease (Ben Haim et al GLIA 2021 PMID: 34396578). ST18 has emerged as a promising marker of pre-myelinating oligodendrocytes (in preparation).
Translational advances include: (1) Generation of a new PLP1 Pelizaeus-Merzbacher Disease (PMD) mouse model to enable in vivo base editing gene therapy testing; (2) Development of direct oligodendrocyte reprogramming from fibroblasts (Tanabe et al Development 2022 PMID: 35748297); (3) Discovery of novel strategies for gene delivery to microglia via myelin protein uptake (Young et al., in press). Finally, (4) our findings also implicate interferon gamma–induced oxidative stress as a driver of MS neuron loss, with inhibitor studies in progress, including plans for a clinical trial. These breakthroughs create new therapeutic horizons for cerebral palsy, leukodystrophy, MS, and stroke by targeting both oligodendrocyte resilience and immune modulation.
Translational advances include: (1) Generation of a new PLP1 Pelizaeus-Merzbacher Disease (PMD) mouse model to enable in vivo base editing gene therapy testing; (2) Development of direct oligodendrocyte reprogramming from fibroblasts (Tanabe et al Development 2022 PMID: 35748297); (3) Discovery of novel strategies for gene delivery to microglia via myelin protein uptake (Young et al., in press). Finally, (4) our findings also implicate interferon gamma–induced oxidative stress as a driver of MS neuron loss, with inhibitor studies in progress, including plans for a clinical trial. These breakthroughs create new therapeutic horizons for cerebral palsy, leukodystrophy, MS, and stroke by targeting both oligodendrocyte resilience and immune modulation.