PDF(Pubmed)
Abstract：
Strategies for treating progressive multiple sclerosis (MS) remain limited. Here, we found that miR-145-5p is overabundant uniquely in chronic lesion tissues from secondary progressive MS patients. We induced both acute and chronic demyelination in miR-145 knockout mice to determine its contributions to remyelination failure. Following acute demyelination, no advantage to miR-145 loss could be detected. However, after chronic demyelination, animals with miR-145 loss demonstrated increased remyelination and functional recovery, coincident with altered presence of astrocytes and microglia within the corpus callosum relative to wild-type animals. This improved response in miR-145 knockout animals coincided with a pathological upregulation of miR-145-5p in wild-type animals with chronic cuprizone exposure, paralleling human chronic lesions. Furthermore, miR-145 overexpression specifically in oligodendrocytes (OLs) severely stunted differentiation and negatively impacted survival. RNAseq analysis showed altered transcriptome in these cells with downregulated major pathways involved in myelination. Our data suggest that pathological accumulation of miR-145-5p is a distinctive feature of chronic demyelination and is strongly implicated in the failure of remyelination, possibly due to the inhibition of OL differentiation together with alterations in other glial cells. This is mirrored in chronic MS lesions, and thus miR-145-5p serves as a potential relevant therapeutic target in progressive forms of MS.
摘要：
治疗进行性多发性硬化症（MS）的策略仍然有限。这里,我们发现miR-145-5p在继发性进展型MS患者的慢性病变组织中含量过多.我们在miR-145敲除小鼠中诱导了急性和慢性脱髓鞘，以确定其对髓鞘再生失败的贡献。急性脱髓鞘后，未检测到miR-145丢失的优势.然而,慢性脱髓鞘后，miR-145丢失的动物表现出增加的髓鞘再生和功能恢复，与野生型动物相比，call体内星形胶质细胞和小胶质细胞的存在发生了变化。miR-145敲除动物中的这种改善的反应与miR-145-5p在具有慢性铜宗暴露的野生型动物中的病理上调相吻合。平行人类慢性病变。此外，miR-145在少突胶质细胞(OLs)中特异性过表达严重阻碍分化并负面影响存活。RNAseq分析显示这些细胞中的转录组改变,与髓鞘形成有关的主要途径下调。我们的数据表明，miR-145-5p的病理积累是慢性脱髓鞘的一个显著特征，并且与髓鞘再生的失败密切相关。可能是由于OL分化的抑制以及其他神经胶质细胞的改变。这反映在慢性MS病变中，因此，miR-145-5p在MS的进行性形式中充当潜在的相关治疗靶标。
