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. Overall design: 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.