Bank of Tissues and Cells, Hospices Civils de Lyon, Hôpital Edouard Herriot, Place d'Arsonval, F-69003 Lyon, France.
Stem-Cell and Brain Research Institute, 18 Avenue de Doyen Lépine, F-69500 Bron, France.
Int J Mol Sci. 2022 Nov 30;23(23):14993. doi: 10.3390/ijms232314993.
In a substantial share of patients suffering from multiple sclerosis (MS), neurological functions slowly deteriorate despite a lack of radiological activity. Such a silent progression, observed in either relapsing-remitting or progressive forms of MS, is driven by mechanisms that appear to be independent from plaque activity. In this context, we previously reported that, in the spinal cord of MS patients, periplaques cover large surfaces of partial demyelination characterized notably by a transforming growth factor beta (TGF-beta) molecular signature and a decreased expression of the oligodendrocyte gene (N-Myc downstream regulated 1). In the present work, we re-assessed a previously published RNA expression dataset in which brain periplaques were originally used as internal controls. When comparing the mRNA profiles obtained from brain periplaques with those derived from control normal white matter samples, we found that, irrespective of plaque activity, brain periplaques exhibited a TGF-beta molecular signature, an increased expression of (transforming growth factor beta 2) and a decreased expression of the oligodendrocyte genes (N-Myc downstream regulated 1) and (myelin-associated glycoprotein). From these data obtained at the mRNA level, a survey of the human proteome allowed predicting a protein-protein interaction network linking TGFB2 to the down-regulation of both and in brain periplaques. To further elucidate the role of NDRG1 in periplaque-associated partial demyelination, we then extracted the interaction network linking NDRG1 to proteins detected in human central myelin sheaths. We observed that such a network was highly significantly enriched in RNA-binding proteins that notably included several HNRNPs (heterogeneous nuclear ribonucleoproteins) involved in the post-transcriptional regulation of . We conclude that both brain and spinal cord periplaques host a chronic process of tissue remodeling, during which oligodendrocyte myelinating functions are altered. Our findings further suggest that TGFB2 may fuel such a process. Overall, the present work provides additional evidence that periplaque-associated partial demyelination may drive the silent progression observed in a subset of MS patients.
在大量多发性硬化症 (MS) 患者中，尽管缺乏影像学活动，但神经功能仍会缓慢恶化。这种在复发缓解型或进展型 MS 中观察到的无声进展是由似乎独立于斑块活动的机制驱动的。在这种情况下，我们之前报道过，在 MS 患者的脊髓中，围绕斑块的区域覆盖了大面积的部分脱髓鞘区域，其特征主要是转化生长因子β (TGF-β) 分子特征和少突胶质细胞基因 (N-Myc 下游调节因子 1) 的表达降低。在本工作中，我们重新评估了之前发表的 RNA 表达数据集，其中脑周围斑块最初被用作内部对照。当比较从脑周围斑块获得的 mRNA 图谱与从对照正常白质样本获得的图谱时，我们发现，无论斑块活动如何，脑周围斑块均表现出 TGF-β分子特征、 (转化生长因子β 2) 表达增加和少突胶质细胞基因 (N-Myc 下游调节因子 1) 和 (髓鞘相关糖蛋白) 表达降低。从这些 mRNA 水平获得的数据中，对人类蛋白质组的调查允许预测一个蛋白质-蛋白质相互作用网络，将 TGFB2 与脑周围斑块中 和 的下调联系起来。为了进一步阐明 NDRG1 在周围斑块相关部分脱髓鞘中的作用，我们然后提取了将 NDRG1 与在人中枢髓鞘鞘中检测到的蛋白质联系起来的相互作用网络。我们观察到，这样的网络在 RNA 结合蛋白中高度显著富集，这些 RNA 结合蛋白特别包括几个 HNRNPs（异质核核糖核蛋白），它们参与 的转录后调节。我们得出结论，脑和脊髓周围斑块都存在组织重塑的慢性过程，在此过程中，少突胶质细胞的髓鞘形成功能发生改变。我们的研究结果进一步表明，TGFB2 可能推动了这一过程。总体而言，本工作提供了额外的证据，表明与周围斑块相关的部分脱髓鞘可能导致在一部分 MS 患者中观察到的无声进展。
