Hefei National Laboratory for Physical Sciences at the Microscale, CAS Key Laboratory of Brain Function and Disease, School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, CAMS and PUMC, Beijing, China.
Cell Death Differ. 2021 Sep;28(9):2634-2650. doi: 10.1038/s41418-021-00774-3. Epub 2021 Mar 24.
The brain is known to express many long noncoding RNAs (lncRNAs); however, whether and how these lncRNAs function in modulating synaptic stability remains unclear. Here, we report a cerebellum highly expressed lncRNA, Synage, regulating synaptic stability via at least two mechanisms. One is through the function of Synage as a sponge for the microRNA miR-325-3p, to regulate expression of the known cerebellar synapse organizer Cbln1. The other function is to serve as a scaffold for organizing the assembly of the LRP1-HSP90AA1-PSD-95 complex in PF-PC synapses. Although somewhat divergent in its mature mRNA sequence, the locus encoding Synage is positioned adjacent to the Cbln1 loci in mouse, rhesus macaque, and human, and Synage is highly expressed in the cerebella of all three species. Synage deletion causes a full-spectrum cerebellar ablation phenotype that proceeds from cerebellar atrophy, through neuron loss, on to synapse density reduction, synaptic vesicle loss, and finally to a reduction in synaptic activity during cerebellar development; these deficits are accompanied by motor dysfunction in adult mice, which can be rescued by AAV-mediated Synage overexpression from birth. Thus, our study demonstrates roles for the lncRNA Synage in regulating synaptic stability and function during cerebellar development.
大脑中已知表达许多长非编码 RNA（lncRNA）；然而，这些 lncRNA 是否以及如何在调节突触稳定性方面发挥作用尚不清楚。在这里，我们报告了一种在小脑中高度表达的 lncRNA，Synage，它通过至少两种机制调节突触稳定性。一种是通过 Synage 作为 microRNA miR-325-3p 的海绵的功能，来调节已知的小脑突触组织者 Cbln1 的表达。另一种功能是作为 LRP1-HSP90AA1-PSD-95 复合物在 PF-PC 突触中组装的支架。尽管其成熟 mRNA 序列有些差异，但编码 Synage 的基因座在小鼠、恒河猴和人类中与 Cbln1 基因座相邻，Synage 在这三种物种的小脑中有高度表达。Synage 缺失导致全谱小脑消融表型，从小脑萎缩开始，通过神经元丧失，到突触密度降低、突触小泡丢失，最后到小脑发育过程中突触活动减少；这些缺陷伴随着成年小鼠的运动功能障碍，可通过从出生开始用 AAV 介导的 Synage 过表达来挽救。因此，我们的研究表明 lncRNA Synage 在调节小脑发育过程中的突触稳定性和功能方面发挥作用。
