# Neuronal responses to chronic demyelination

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $364,324

## Abstract

PROJECT SUMMARY
Oligodendrocytes are a highly specialized type of glial cell that myelinates axons of the vertebrate CNS, both
promoting rapid transmission of nerve impulses via saltatory conduction and providing metabolic and trophic
support for the axons. A widely held consensus view in the field holds that the loss of this oligodendrocyte
support (as seen in demyelinating conditions such as multiple sclerosis) directly contributes to axonal loss and
cumulative disability. Nevertheless, direct experimental evidence for oligodendrocyte support being required for
axonal survival is largely lacking. In addition, there is remarkably little information available on how neurons
respond to a primary demyelinating insult. To better understand whether loss of oligodendrocyte support of
axons directly leads to axonal loss or neuronal changes, we will capitalize on two tamoxifen-inducible
conditional knockout mouse strains for the Myrf gene, which encodes a transcription factor required for
myelination and myelin maintenance. The Myrf∆iPLP mouse line leads to oligodendrocyte loss and severe CNS
demyelination, but largely remyelinates through recruitment of non-recombined OPCs. In contrast, the
Myrf∆iSox10 mouse line shows near complete CNS demyelination with remyelination failure, representing a
unique mouse model of severe and chronic demyelination.
Based on our preliminary data we hypothesize that neurons are initially resilient to even severe demyelinating
insults, but that they become vulnerable to loss in the face of subsequent remyelination failure, inflammation or
metabolic challenge. In addition, we have found activation of the DLK/JNK/c-Jun axonal stress pathway in
chronically demyelinated animals, providing a potential molecular signal linking chronic demyelination to
neurodegeneration. We will use retinal ganglion cells (RGCs) in these mice as the ideal myelinated neuronal
population to: 1) determine the relative roles of remyelination failure, neuroinflammation and metabolic
challenge in inducing neurodegeneration; 2) establish the role of the DLK/JNK/c-Jun in mediating neuronal
changes following loss of oligodendrocyte support and 3) Use bulk and single cell RNA-Seq to determine the
transcriptional changes in RGCs in response to loss of glial support and to determine whether specific
subgroups of RGCs show preferential vulnerability to demyelination.

## Key facts

- **NIH application ID:** 10177745
- **Project number:** 1R01NS120981-01
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Ben Emery
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $364,324
- **Award type:** 1
- **Project period:** 2021-04-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10177745

## Citation

> US National Institutes of Health, RePORTER application 10177745, Neuronal responses to chronic demyelination (1R01NS120981-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10177745. Licensed CC0.

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