Reduced Expression of Oligodendrocyte Linage-Enriched Transcripts During the Endoplasmic Reticulum Stress/Integrated Stress Response

ASN Neuro, 2024 · DOI: https://doi.org/10.1080/17590914.2024.2371162 · Published: January 1, 2024

Simple Explanation

The study investigates how endoplasmic reticulum (ER) stress affects oligodendrocytes (OLs), which are crucial for myelin formation in the central nervous system. ER stress is implicated in CNS diseases such as spinal cord injury and multiple sclerosis. Researchers used drugs (thapsigargin and tunicamycin) to induce ER stress in rat OL precursor cells and analyzed changes in gene expression. They found that ER stress downregulates genes important for OL identity and myelination. The study also observed similar gene expression changes in mouse models of white matter diseases, suggesting that persistent ER stress can disrupt OL function and contribute to myelin degeneration.

Study Duration

Not specified

Participants

Primary rat oligodendrocyte precursor cells (OPCs), mouse models of white matter pathologies

Evidence Level

Not specified

Key Findings

1
ER stress, induced by thapsigargin (TG) and tunicamycin (TM), downregulates oligodendrocyte (OL) lineage-enriched mRNAs, including those for transcription factors (TFs) that drive OL identity, such as Olig2.
2
Tunicamycin is a more selective inducer of ER stress than thapsigargin in OPCs. ERSR-associated downregulation of the OL lineage-specific gene expression is another major finding from the current analysis.
3
In mouse models of white matter pathologies, ER stress is associated with decreased OL-specific gene expression, suggesting a link between ER stress and myelin degeneration.

Research Summary

This study analyzes the transcriptomic effects of ER stress induced by thapsigargin (TG) and tunicamycin (TM) in primary rat oligodendrocyte precursor cells (OPCs). The results show that both drugs upregulate genes associated with stress response, but tunicamycin is a more selective inducer of ER stress. A key finding is the downregulation of oligodendrocyte lineage-enriched mRNAs, including transcription factors like Olig2, by both TG and TM. This suggests that ER stress compromises the transcriptomic identity of the OL lineage. Further analysis of mouse models with white matter pathologies revealed decreased expression of OL-specific genes under ER stress, indicating that persistent, pathological ER stress may negatively impact the structural and/or functional integrity of white matter.

Practical Implications

Therapeutic Targeting

Targeting ER stress in oligodendrocytes may offer a therapeutic strategy for treating white matter diseases like multiple sclerosis and spinal cord injury.

Understanding Disease Mechanisms

The study provides insights into the molecular mechanisms by which ER stress contributes to myelin degeneration and oligodendrocyte dysfunction.

Drug Development

The finding that tunicamycin is a more selective ER stress inducer than thapsigargin may guide the selection of drugs for studying ER stress in oligodendrocyte lineage cells.

Study Limitations

1
The study uses in vitro models and mouse models, which may not fully replicate the complexity of human white matter diseases.
2
The study focuses on specific ER stress inducers (TG and TM), and other mechanisms of ER stress may have different effects.
3
The study identifies correlations between ER stress and gene expression but does not establish causation.

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