# Loss of oligodendrocyte transcription factor 2 protein expression in metabolically stressed oligodendrocytes

## TL;DR

This study shows that stressed oligodendrocytes lose a key protein (OLIG2), which could be an early sign of myelin damage in diseases like multiple sclerosis.

## Contribution

The study identifies a post-transcriptional loss of OLIG2 in stressed oligodendrocytes as a novel early indicator of cell stress in demyelinating diseases.

## Key findings

- Stressed oligodendrocytes show reduced OLIG2 protein without changes in mRNA levels.
- OLIG2 loss occurs in both animal models and human MS lesions.
- Pharmacological intervention can reduce OLIG2 loss in stressed cells.

## Abstract

Oligodendrocytes are essential for myelin production, maintenance, and repair, and their dysfunction contributes to the pathogenesis of demyelinating diseases such as multiple sclerosis (MS). Here, we identify an early stress-associated oligodendrocyte state characterized by a rapid, post-transcriptional loss of the lineage-defining transcription factor Oligodendrocyte Transcription Factor 2 (OLIG2). Using the cuprizone model of toxic demyelination, we observed an early appearance of OLIG2low expressing oligodendrocytes, followed by the emergence of OLIG2-negative oligodendrocytes at later stages. This observation was particularly pronounced among cells expressing the integrated stress response marker Activating Transcription Factor 3 (ATF3). Transcriptomic analysis, quantitative PCR, and combined in situ hybridization–immunohistochemistry confirmed that these changes occurred without a corresponding reduction in Olig2 mRNA levels, indicating that OLIG2 protein loss is a stress-induced, post-transcriptional event not captured by RNA-level profiling. A similar phenotype was observed in a reversible metabolic stress paradigm (i.e., chronic starvation model) and in post-mortem MS lesions, where stressed oligodendrocytes showed reduced or absent OLIG2 protein expression. Pharmacological intervention with the sphingosine-1-phosphate receptor modulator siponimod during cuprizone intoxication attenuated OLIG2 protein loss, indicating that this stress-induced state is pharmacologically modifiable. These findings reveal a transient and potentially reversible phenotype in stressed oligodendrocytes that may precede overt cell loss or demyelination. Thus, OLIG2 protein loss may serve as an early indicator of oligodendrocyte stress and a possible therapeutic target for preserving myelin integrity in demyelinating disorders. These findings have additional methodological implications as stressed oligodendrocytes may evade detection using OLIG2-based lineage markers.

The online version contains supplementary material available at 10.1007/s00401-026-03000-x.