Functional genomic analyses highlight a shift in Gpr17-regulated cellular processes in oligodendrocyte progenitor cells and underlying myelin dysregulation in the aged mouse cerebrum.
Functional genomic analyses highlight a shift in Gpr17-regulated cellular processes in oligodendrocyte progenitor cells and underlying myelin dysregulation in the aged mouse cerebrum.
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DOI：
10.1111/acel.13335
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发表时间：
2021-04
期刊：
影响因子：
7.8
通讯作者：
Butt AM
中科院分区：
文献类型：
--
作者：
Rivera AD;Pieropan F;Chacon-De-La-Rocha I;Lecca D;Abbracchio MP;Azim K;Butt AM
大脑老化的特征是神经元功能下降和相关的认知缺陷。越来越多的证据表明，髓鞘破坏是导致与年龄相关的脑可塑性和修复反应丧失的重要因素。在大脑中，髓鞘是由少突胶质细胞产生的，少突胶质细胞是由少突胶质祖细胞（OPC）在整个生命过程中产生的。目前，一个主要的假设指出，衰老是多发性硬化症（MS）髓鞘再生最终崩溃的主要原因。然而，对大脑衰老的细胞和分子过程的不完全理解阻碍了再生策略的发展。在这里，我们结合系统生物学和神经生物学方法证明，少突胶质细胞和髓鞘基因是衰老小鼠大脑中变化最大的基因之一。这是强调了确定的因果关系之间的联系信号通路和下游转录网络，定义少突胶质细胞破坏老化。结果强调，G蛋白偶联受体Gpr17是衰老过程中OPCs破坏的核心，这一点已通过遗传命运图谱和细胞分析得到证实。最后，我们使用系统生物学策略来鉴定在年龄相关的神经病理学背景下使OPCs年轻化并恢复髓鞘形成的治疗剂。老化减少了OPC的数量和它们的“干性”。基因组分析解决了支持OPCs年龄相关性下降的关键机制，最显著的是Gpr17在分化定向OPCs亚群中的表达减少。药物基因组学鉴定了具有使OPCs年轻化并促进髓鞘形成和修复的潜力的小分子。
Brain ageing is characterised by a decline in neuronal function and associated cognitive deficits. There is increasing evidence that myelin disruption is an important factor that contributes to the age‐related loss of brain plasticity and repair responses. In the brain, myelin is produced by oligodendrocytes, which are generated throughout life by oligodendrocyte progenitor cells (OPCs). Currently, a leading hypothesis points to ageing as a major reason for the ultimate breakdown of remyelination in Multiple Sclerosis (MS). However, an incomplete understanding of the cellular and molecular processes underlying brain ageing hinders the development of regenerative strategies. Here, our combined systems biology and neurobiological approach demonstrate that oligodendroglial and myelin genes are amongst the most altered in the ageing mouse cerebrum. This was underscored by the identification of causal links between signalling pathways and their downstream transcriptional networks that define oligodendroglial disruption in ageing. The results highlighted that the G‐protein coupled receptor Gpr17 is central to the disruption of OPCs in ageing and this was confirmed by genetic fate‐mapping and cellular analyses. Finally, we used systems biology strategies to identify therapeutic agents that rejuvenate OPCs and restore myelination in age‐related neuropathological contexts. Ageing reduces the number of OPCs and their ‘stemness’. Genomic analysis resolved key mechanisms underpinning the age related decline in OPCs, most notably reduced expression of Gpr17 in a subpopulation of differentiation committed OPCs. Pharmacogenomics identified small molecules that have the potential to rejuvenate OPCs and promote myelination and repair.
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影响因子：
6.2
作者：
Figlia G;Gerber D;Suter U
通讯作者：
Suter U
影响因子：
9.8
作者：
Azim K;Angonin D;Marcy G;Pieropan F;Rivera A;Donega V;Cantù C;Williams G;Berninger B;Butt AM;Raineteau O
通讯作者：
Raineteau O
DOI：
10.1074/mcp.ra120.002102
发表时间：
2020-08
期刊：
Molecular & cellular proteomics : MCP
影响因子：
--
作者：
de la Fuente AG;Queiroz RML;Ghosh T;McMurran CE;Cubillos JF;Bergles DE;Fitzgerald DC;Jones CA;Lilley KS;Glover CP;Franklin RJM
通讯作者：
Franklin RJM
影响因子：
8.8
作者：
Chen, Ting-Jiun;Kula, Bartosz;Kukley, Maria
通讯作者：
Kukley, Maria
影响因子：
6.2
作者：
Beyer, Felix;Jadasz, Janusz;Kuery, Patrick
通讯作者：
Kuery, Patrick