Reduced Expression of Oligodendrocyte Linage-Enriched Transcripts During the Endoplasmic Reticulum Stress/Integrated Stress Response DOI Creative Commons
Yonglin Gao,

Łukasz P. Słomnicki,

Ewa Kilańczyk

et al.

ASN NEURO, Journal Year: 2024, Volume and Issue: 16(1)

Published: Jan. 1, 2024

Endoplasmic reticulum (ER) stress in oligodendrocyte (OL) linage cells contributes to several CNS pathologies including traumatic spinal cord injury (SCI) and multiple sclerosis. Therefore, primary rat OL precursor cell (OPC) transcriptomes were analyzed using RNASeq after treatments with two ER stress-inducing drugs, thapsigargin (TG) or tunicamycin (TM). Gene ontology term (GO) enrichment showed that both drugs upregulated mRNAs associated the general response. The GOs related only enriched for TM-upregulated mRNAs, suggesting greater selectivity of TM. Both TG TM downregulated cycle/cell proliferation-associated transcripts, indicating anti-proliferative effects stress. Interestingly, many lineage-enriched downregulated, those transcription factors drive identity such as Olig2. Moreover, stress-associated decreases OL-specific gene expression found mature OLs from mouse models white matter contusive SCI, toxin-induced demyelination, Alzheimer's disease-like neurodegeneration. Taken together, disrupted transcriptomic fingerprint lineage may facilitate myelin degeneration and/or dysfunction when pathological persists cells.

Language: Английский

Discovery of a Novel Series of Homo sapiens Caseinolytic Protease P Agonists for Colorectal Adenocarcinoma Treatment via ATF3-Dependent Integrated Stress Response DOI
Jiangnan Zhang, Zhiqiang Qiu, Song Liu

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(4), P. 2812 - 2836

Published: Feb. 8, 2024

Homo sapiens caseinolytic protease P (HsClpP) activation is a promising strategy for colon cancer treatment. In this study, CCG1423 was identified as selective activator of HsClpP. After optimization, NCA029 emerged the most potent compound, with an EC50 0.2 μM against Molecular dynamics revealed that affinity YYW aromatic network crucial its selectivity toward Furthermore, displayed favorable pharmacokinetics and safety profiles significantly inhibited tumor growth in HCT116 xenografts, resulting 83.6% inhibition. Mechanistically, targeted HsClpP, inducing mitochondrial dysfunction activating ATF3-dependent integrated stress response, ultimately causing cell death colorectal adenocarcinoma. These findings highlight effective HsClpP potential therapy.

Language: Английский

Citations

5
Reduced White Matter Damage and Lower Neuroinflammatory Potential of Microglia and Macrophages in Hri/Eif2ak1−/− Mice After Contusive Spinal Cord Injury DOI Open Access
Sujata Saraswat Ohri,

Scott A. Myers,

Benjamin Rood

et al.

Glia, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 6, 2025

Cellular stressors inhibit general protein synthesis while upregulating stress response transcripts and/or proteins. Phosphorylation of the translation factor eIF2α by one several stress-activated kinases is a trigger for such signaling, known as integrated (ISR). The ISR regulates cell survival and function under stress. Here, germline knockout mice were used to determine contributions three major kinases, HRI/EIF2AK1, GCN2/EIF2AK4, PKR//EIF2AK2, pathogenesis moderate contusive spinal cord injury (SCI) at thoracic T9 level. One-day post-injury (dpi), reduced levels peIF2α found in Hri

Language: Английский

Citations

0
Enhancer Dynamics and Spatial Organization Drive Anatomically Restricted Cellular States in the Human Spinal Cord DOI Creative Commons

Elena Kandror,

Anqi Wang, Mathieu Carrière

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 11, 2025

SUMMARY Here, we report the spatial organization of RNA transcription and associated enhancer dynamics in human spinal cord at single-cell single-molecule resolution. We expand traditional multiomic measurements to reveal epigenetically poised bivalent active transcriptional states that define cell type specification. Simultaneous detection chromatin accessibility histone modifications nuclei reveals previously unobserved cell-type specific cryptic activity, which activation is uncoupled from accessibility. Such enhancers both stable identity transitions between cells undergoing differentiation. also glial gene regulatory networks reorganize along rostrocaudal axis, revealing anatomical differences regulation. Finally, identify into distinct cellular organizations address functional significance this observation context paracrine signaling. conclude diversity best captured through lens state intercellular interactions drive state. This study provides fundamental insights healthy cord.

Language: Английский

Citations

0
Oligodendrocyte‐selective deletion of the eIF2α kinase Perk/Eif2ak3 limits functional recovery after spinal cord injury DOI
Sujata Saraswat Ohri, Michael D. Forston,

Scott A. Myers

et al.

Glia, Journal Year: 2024, Volume and Issue: 72(7), P. 1259 - 1272

Published: April 8, 2024

After spinal cord injury (SCI), re-establishing cellular homeostasis is critical to optimize functional recovery. Central that response PERK signaling, which ultimately initiates a pro-apoptotic if cannot be restored. Oligodendrocyte (OL) loss and white matter damage drive consequences determine recovery potential after thoracic contusive SCI. We examined acute (<48 h post-SCI) chronic (6 weeks effects of conditionally deleting Perk from OLs prior While transcript expressed in many types cells the adult cord, its levels are disproportionately high OL lineage cells. Deletion OL-Perk SCI resulted in: (1) enhanced phosphorylation eIF2α, major substrate mediator integrated stress (ISR), (2) expression downstream ISR genes Atf4, Ddit3/Chop, Tnfrsf10b/Dr5, (3) reduced lineage-specific Olig2 mRNA, but not neuronal or astrocytic mRNAs, (4) chronically decreased content spared at epicenter, (5) impaired hindlimb locomotor recovery, (6) epicenter sparing. Cultured primary precursor with activated ER showed: unaffected gene induction, increased cytotoxicity. Therefore, deficiency exacerbates signaling potentiates The latter effect likely mediated by

Language: Английский

Citations

3
Plant-derived bioactive compounds and their novel role in central nervous system disorder treatment via ATF4 targeting: A systematic literature review DOI Open Access
Nan Zhang, Shun Zhang, Xiaoyu Dong

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 176, P. 116811 - 116811

Published: May 24, 2024

Central nervous system (CNS) disorders exhibit exceedingly intricate pathogenic mechanisms. Pragmatic and effective solutions remain elusive, significantly compromising human life health. Activating transcription factor 4 (ATF4) participates in the regulation of multiple pathophysiological processes, including CNS disorders. Considering widespread involvement ATF4 pathological process disorders, targeted by plant-derived bioactive compounds (PDBCs) may become a viable strategy for treatment However, regulatory relationship between PDBCs remains incompletely understood. Here, we aimed to comprehensively review studies on targeting ameliorate thereby offering novel directions insights A computerized search was conducted PubMed, Embase, Web Science, Google Scholar databases identify preclinical experiments related The timeframe from inception December 2023. Two assessors searches using keywords "ATF4," "Central Nervous System," "Neurological," "Alzheimer's disease," "Parkinson's Disease," "Stroke," "Spinal Cord Injury," "Glioblastoma," "Traumatic Brain Injury." Overall, 31 were included, encompassing assessments 27 PDBCs. Combining results vivo vitro studies, observed that these PDBCs, via modulation, prevent deposition amyloid-like fibers such as Aβ, tau, α-synuclein. They regulate ERS, reduce release inflammatory factors, restore mitochondrial membrane integrity oxidative stress, synaptic plasticity, modulate autophagy, engage anti-apoptotic Consequently, they exert neuroprotective effects Numerous have shown potential facilitating restoration functionality, presenting expansive prospects future endeavors necessitate high-quality, large-scale, comprehensive clinical further validate this therapeutic potential.

Language: Английский

Citations

2
Reduced Expression of Oligodendrocyte Linage-Enriched Transcripts During the Endoplasmic Reticulum Stress/Integrated Stress Response DOI Creative Commons
Yonglin Gao,

Łukasz P. Słomnicki,

Ewa Kilańczyk

et al.

ASN NEURO, Journal Year: 2024, Volume and Issue: 16(1)

Published: Jan. 1, 2024

Endoplasmic reticulum (ER) stress in oligodendrocyte (OL) linage cells contributes to several CNS pathologies including traumatic spinal cord injury (SCI) and multiple sclerosis. Therefore, primary rat OL precursor cell (OPC) transcriptomes were analyzed using RNASeq after treatments with two ER stress-inducing drugs, thapsigargin (TG) or tunicamycin (TM). Gene ontology term (GO) enrichment showed that both drugs upregulated mRNAs associated the general response. The GOs related only enriched for TM-upregulated mRNAs, suggesting greater selectivity of TM. Both TG TM downregulated cycle/cell proliferation-associated transcripts, indicating anti-proliferative effects stress. Interestingly, many lineage-enriched downregulated, those transcription factors drive identity such as Olig2. Moreover, stress-associated decreases OL-specific gene expression found mature OLs from mouse models white matter contusive SCI, toxin-induced demyelination, Alzheimer's disease-like neurodegeneration. Taken together, disrupted transcriptomic fingerprint lineage may facilitate myelin degeneration and/or dysfunction when pathological persists cells.

Language: Английский

Citations

0