# Jun O-GlcNAcylation Regulates Schwann Cell Injury Response

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $411,521

## Abstract

Project Summary/Abstract: Peripheral neuropathy is an increasingly common disorder that affects up to 25%
of diabetics and 35-40% of elderly individuals. The pathological underpinning of peripheral neuropathy from
any etiology is the loss of axonal integrity and function. In diabetics and the aged, the axonal loss is
accompanied by impaired nerve fiber regeneration after injury; a state that is recapitulated in rodent models.
Axonal injury triggers a dramatic reprogramming of the Schwann cells (SCs) surrounding the damaged axon
that culminates in the adoption of a `repair SC' phenotype. The repair SC promotes axon/myelin breakdown
and disposal, attracts macrophages, and produces neurotrophic factors. Upon contact with the regenerating
axon, it transforms back into a differentiated SC to ensure remyelination or Remak bundle formation. The
primary regulator of this transition to the repair SC is the transcription factor JUN, which is rapidly activated
after injury in SCs surrounding damaged axons. In Jun-deficient mice, nerve regeneration is impaired.
 In keeping with the impaired axon regeneration in diabetic and aged animals, we find that mice with
mutations that alter SC metabolism fail to effectively promote nerve regeneration. Most recently, we
characterized OGT-SCKO mice that lack SC expression of O-GlcNAc transferase (OGT), the enzyme that
catalyzes addition of O-GlcNAc moieties to proteins at Ser and Thr residues. OGT activity is regulated by the
flux of glucose through the hexosamine biosynthetic pathway, thus it serves as a sensor that aggregates
information regarding glucose metabolism and transmits it into changes in cell physiology. Notably, abnormal
O-GlcNAcylation has been implicated in diabetes, cancer, and neurodegenerative diseases. Mice lacking O-
GlcNAcylation in SCs develop a tomaculous demyelinating neuropathy. Expression profiling of OGT-SCKO
sciatic nerve revealed high expression of many AP-1 targets. Moreover, we find that JUN phosphorylation and
transcriptional activity are regulated by O-GlcNAcylation. In keeping with abnormalities in JUN activity, we find
that loss of OGT leads to a substantial decrease in regeneration/remyelination, indicating that the SC injury
response is modulated by metabolism. These results lead us to hypothesize that poor nerve regeneration, and
potentially the neuropathy itself, in diabetic and aged individuals is caused by the impact of abnormal
metabolism on the generation, function, and/or cessation of the SC injury response via direct effects on JUN
activity. To pursue this hypothesis we propose three aims: 1) To investigate how metabolism impacts the SC
injury response; 2) To investigate the role of O-GlcNAcylation in regulating JUN activity; and 3) To determine
the role of AP-1 partners and other regulators in the SC injury response. Through these studies, we hope to
show that therapies targeting Schwann cells and their repair functions will be useful in treating peripheral
neuropathy and t...

## Key facts

- **NIH application ID:** 10150110
- **Project number:** 5R01NS105645-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** JEFFREY D MILBRANDT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $411,521
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10150110

## Citation

> US National Institutes of Health, RePORTER application 10150110, Jun O-GlcNAcylation Regulates Schwann Cell Injury Response (5R01NS105645-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10150110. Licensed CC0.

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