Single nucleus RNA Sequencing of nontransgenic and Huntington's disease R6/2 mouse striatum and cortex

A challenge in treating Huntington's disease (HD) is the complexity of affected brain regions and cell types. We carried out a systematic analysis of cell type-specific changes in cortex and striatum from R6/2 mice at 8 and 12w, and discovered major expression changes in oligodendrocytes (OLs) and oligodendrocyte precursors (OPCs), suggesting that many OLs were arrested in an immature state. Causal gene network analysis implicates PRKCE and SWI/SNF in abnormal OL maturation. PRKCE protein was dramatically decreased. Disrupted cell-to-cell signaling between medium spinyneurons and OL that may contribute to neuronal dysfunction was identified in R6/2 mice using ligand-receptor analysis. These findings reveal novel insights into OL pathology, span multiple brain regions in humans and mice and suggest therapeutic strategies. Single Nucleus RNA-Seq of NT and R62 mouse striatum and cortex. snucRNAseq profiles of NT and R6/2 striatum and cortex were generated with the 10x genomics platform and sequenced using the Illumina Hiseq 4000.

亨廷顿舞蹈症（Huntington's disease, HD）治疗的一大难点在于其受累脑区与细胞类型的复杂性。我们对8周龄和12周龄的R6/2小鼠的皮层与纹状体开展了系统性分析，探究其细胞类型特异性的分子变化，发现少突胶质细胞（oligodendrocytes, OLs）与少突胶质前体细胞（oligodendrocyte precursors, OPCs）存在显著的表达改变，提示大量少突胶质细胞停滞于未成熟状态。因果基因网络分析显示，PRKCE与SWI/SNF复合物参与了异常的少突胶质细胞成熟过程，且PRKCE蛋白水平大幅下降。通过配体-受体分析，我们在R6/2小鼠中发现中型多棘神经元与少突胶质细胞之间的细胞间信号传导紊乱，该紊乱可能参与神经元功能异常的发生。上述发现为少突胶质细胞的病理机制提供了全新见解，研究覆盖人类与小鼠的多个脑区，并为治疗策略的研发提供了新思路。本数据集包含NT与R6/2小鼠纹状体、皮层的单细胞核RNA测序（Single Nucleus RNA-Seq, snucRNAseq）数据。我们使用10x Genomics平台构建了NT与R6/2小鼠纹状体及皮层的snucRNAseq文库，并通过Illumina HiSeq 4000完成测序。