In a recent paper, published in Nature Communications, a team of scientists used single nucleus RNA sequencing (snRNAseq) to investigate the molecular pathology of Huntington’s disease. Changes in glucose and lipid metabolism were linked to abnormal cell maturation, with protein kinase C epsilon (PRKCE) and thiamine pyrophosphokinase 1 (TPK1) identified as important genes. A role for thiamine and biotin treatment was also established as a method for restoring pathological changes.
Utilising single nucleus sequencing
Huntington’s disease (HD) is a progressive neurodegenerative disorder that results in cognitive, psychiatric and movement impairments. Recent single-cell transcriptomic studies have shown cell type-specific neurodevelopmental impairments in HD. One type of cells that have been explored are oligodendrocytes (OLs). OLs and other cells of OL lineage, such as oligodendrocyte progenitor cells (OPCs), are of increasing research interest as they have been suggested to be abnormal in HD. For example, post-mortem examination of HD brains revealed an increased density of OLs in the caudate nucleus, including in pre-symptomatic HD patients.
In the current study, the researchers used snRNAseq to obtain cell type-specific gene expression data across multiple brain regions from a rapidly progressing mouse model (R6/2) and human post-mortem brain samples (see Figure 1). This analysis aimed to further explore prior results regarding OL maturation deficits, reveal additional insights into cell type-specific signatures and increase the understanding of the key drivers of OL impairments.
Revealing underlying metabolism
The snRNAseq data was used for correlative and causal network modelling. Consistent with the previous literature, OL-lineage cells showed significant transcriptional dysregulation, including altered expression of development and maturation genes. Key drivers were identified that correlated with CAG repeat length in human tissue, a mechanism that underlies the development of HD symptoms.
Due to its downregulation in both human and mouse tissue, PRKCE was identified as a central gene in the OPC/OL causal network. PRKCE codes for a signalling protein, which interacts with SMARCA2 and OLIG2, both important in OL maturation. Functional studies validated the role of PRKCE in OL maturation and these findings were supported with ATACseq data. Additionally, impairments in glucose and lipid metabolism were suggested as potential drivers of this pathology.
The connection to metabolism led the researchers to explore thiamine and biotin metabolic processes within HD and OL maturation impairments. TPK1 converts thiamine into thiamine pyrophosphate and was differentially expressed in most cell types in R6/2 mice. Both TPK1 and SLC19A2, a thiamine transporter, were also downregulated in human HD.
A novel treatment in the future
Further examination of the potential connections between early metabolic changes in HD and OL maturation was performed using thiamine and biotin treatments and additional snRNAseq analysis. The treatment produced a significant recovery of the OL dys-maturation signatures and an overall decrease in the number of significantly differentially expressed genes.
The data from this study further supports thiamine and biotin as a viable treatment for HD, which is currently undergoing a clinical trial in Spain. The authors also highlight the possibility of using single-cell approaches to guide therapeutic target identification and evaluation in the future.
