Abstract:
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 with the general stress response. The GOs related to ER stress were only enriched for TM-upregulated mRNAs, suggesting greater ER stress selectivity of TM. Both TG and TM downregulated cell cycle/cell proliferation-associated transcripts, indicating the anti-proliferative effects of ER stress. Interestingly, many OL lineage-enriched mRNAs were downregulated, including those for transcription factors that drive OL identity such as Olig2. Moreover, ER stress-associated decreases of OL-specific gene expression were found in mature OLs from mouse models of white matter pathologies including contusive SCI, toxin-induced demyelination, and Alzheimer\'s disease-like neurodegeneration. Taken together, the disrupted transcriptomic fingerprint of OL lineage cells may facilitate myelin degeneration and/or dysfunction when pathological ER stress persists in OL lineage cells.
The ER stress response compromises the transcriptomic identity of the OL lineage. Therefore, persistent, pathological ER stress may have a negative impact on structural and/or functional integrity of the white matter.
摘要:
少突胶质细胞(OL)谱系细胞中的内质网(ER)应激有助于几种CNS病理,包括创伤性脊髓损伤(SCI)和多发性硬化症。因此,原代大鼠OL前体细胞(OPC)转录组使用两种ER应激诱导药物处理后,使用RNASeq进行分析,thapsigargin(TG)或衣霉素(TM)。基因本体论项(GO)富集表明,两种药物都上调了与一般应激反应相关的mRNA。与ER胁迫相关的GO仅富集TM上调的mRNA,表明TM的ER胁迫选择性更大。TG和TM均下调细胞周期/细胞增殖相关转录本,表明内质网应激的抗增殖作用。有趣的是,许多富含OL谱系的mRNA被下调,包括那些驱动OL同一性的转录因子,如Olig2。此外,ER应激相关的OL特异性基因表达的降低在白质病变的小鼠模型中发现,包括挫伤性SCI,毒素诱导的脱髓鞘,和老年痴呆症的疾病样神经变性。一起来看,当OL谱系细胞中病理性ER应激持续存在时,OL谱系细胞的转录组指纹图谱破坏可能促进髓鞘变性和/或功能障碍.
ER应激反应损害了OL谱系的转录组同一性。因此,持久性,病理性内质网应激可能对白质的结构和/或功能完整性产生负面影响.