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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE180294 | GEO | 2022/11/14

REPOSITORIES: GEO

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Single nuclei RNAseq analysis of HD mouse model and human brain reveals impaired 1 oligodendrocyte maturation and potential causal regulators

Project description: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 in three regions of human HD post-mortem tissue using single nucleus RNA sequencing. We 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 in mouse and human HD, and its regulator, diacylglycerol lipids, were decreased in human HD at very early stages. ATACseq of mouse glia showed increased accessibility of sites regulated by SWI/SNF subunit Smarca4 in HD, further implicating Prkce-SWI/SNF. We identified differences between 8w and 12w mice in the induction of OPC 37 maturation, with 12w mice most similar to human. Disrupted cell-to-cell signaling between medium spiny neurons and OL, that may contribute to neuronal dysfunction, was identified in both human HD and R6/2 mice using ligand-receptor analysis. These findings reveal novel insights into OL pathology that spans multiple brain regions in humans and mice and suggest therapeutic strategies.

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Project description:Huntington’s disease is a genetic disease caused by a single mutation. It is characterised by progressive movement, emotional and cognitive deficits. R6/2 transgenic mice carrying the Huntington’s disease mutation have a progressive neurological phenotype, including deterioration in cognitive function. The mechanism underlying the cognitive deficits in R6/2 mice is unknown, but dysregulated gene expression, reduced neurotransmitter levels and abnormal synaptic function are present before the cognitive decline becomes pronounced. Our goal here was to ameliorate the cognitive phenotype in R6/2 mice using a combination drug therapy (tacrine, moclobemide and creatine) aimed boosting neurotransmitter levels in the brain. Treatment from 5 weeks of age prevented deterioration in two different cognitive tasks until at least 12 weeks. However, motor deterioration continued unabated. Microarray analysis of global gene expression revealed that many genes significantly up- or down-regulated in untreated R6/2 mice had returned towards normal levels after treatment. Thus dysregulated gene expression was reversed by the combination treatment in the R6/2 mice and probably underlies the observed improvements in cognitive function. Our study shows that cognitive decline caused by a genetic mutation can be slowed by a combination drug treatment, and gives hope that cognitive symptoms in HD can be treated. Keywords = HD Keywords = Huntingtin Keywords = cognitive disorder Keywords = R6/2 Keywords = transgenic mice Keywords = gene expression Keywords = microarray Keywords: ordered

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Targeting H3K4 methylation as a therapeutic strategy for Huntington's disease (RNA-seq)

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