Potential Role of Endoplasmic Reticulum Stress in Modulating Protein Homeostasis in Oligodendrocytes to Improve White
1Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China.
Insights
Preterm white matter injury (WMI) involves oligodendrocyte dysfunction. The unfolded protein response (UPR) attempts to restore protein homeostasis, offering therapeutic targets for WMI.
Area of Science:
- Neuroscience
- Cell Biology
- Developmental Biology
Background:
- Preterm white matter injury (WMI) is a critical condition in premature infants, characterized by demyelination and high mortality.
- Oligodendrocytes (OLs), responsible for myelin production, are vulnerable to disruptions in protein homeostasis due to their reliance on endoplasmic reticulum (ER) quality control.
- ER stress disrupts OL function and survival, impacting myelination during white matter development.
Purpose of the Study:
- To review the current understanding of ER stress in OLs and its role in maintaining protein homeostasis and myelination.
- To explore the pathophysiology of WMI, focusing on ER stress-induced OL dysfunction.
- To discuss potential therapeutic strategies targeting ER stress pathways for WMI treatment.
Main Methods:
- Literature review synthesizing current research on ER stress, UPR, and OLs.
- Analysis of molecular mechanisms underlying ER stress in OLs, including UPR pathways (IRE1/XBP1s, PERK/eIF2α, ATF6).
- Examination of ER stress-related factors like calcium homeostasis, mitochondrial ROS, and autophagy in OL function.
Main Results:
- ER stress significantly impacts OL protein homeostasis, leading to dysfunction and cell death in WMI.
- The unfolded protein response (UPR) is activated to counteract ER stress but can be overwhelmed in severe WMI.
- ER signaling pathways influence calcium, mitochondria, and autophagy, all critical for OL health and myelination.
Conclusions:
- ER stress is a key factor in the pathophysiology of preterm WMI.
- Targeting ER stress and restoring UPR function in OLs presents a promising therapeutic avenue for WMI.
- Further research into ER stress mechanisms can elucidate novel strategies to improve myelination and neurological outcomes in preterm infants.
Abstract:
Preterm white matter injury (WMI) is a demyelinating disease with high incidence and mortality in premature infants. Oligodendrocyte cells (OLs) are a specialized glial cell that produces myelin proteins and adheres to the axons providing energy and metabolic support which susceptible to endoplasmic reticulum protein quality control. Disruption of cellular protein homeostasis led to OLs dysfunction and cell death, immediately, the unfolded protein response (UPR) activated to attempt to restore the protein homeostasis via IRE1/XBP1s, PERK/eIF2α and ATF6 pathway that reduced protein translation, strengthen protein-folding capacity, and degraded unfolding/misfolded protein. Moreover, recent works have revealed the conspicuousness function of ER signaling pathways in regulating influenced factors such as calcium homeostasis, mitochondrial reactive oxygen generation, and autophagy activation to regulate protein hemostasis and improve the myelination function of OLs. Each of the regulation modes and their corresponding molecular mechanisms provides unique opportunities and distinct perspectives to obtain a deep understanding of different actions of ER stress in maintaining OLs' health and function. Therefore, our review focuses on summarizing the current understanding of ER stress on OLs' protein homeostasis micro-environment in myelination during white matter development, as well as the pathophysiology of WMI, and discussing the further potential experimental therapeutics targeting these factors that restore the function of the UPR in OLs myelination function.
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