Huntington disease oligodendrocyte maturation deficits revealed by single-nucleus RNAseq are rescued by thiamine-biotin supplementation.
Ryan G LimOsama Al-DalahmahJie WuMaxwell P GoldJack C ReidlingGuomei TangMiriam AdamDavid K DansuHye-Jin ParkPatrizia CasacciaRicardo MiramontesAndrea M Reyes-OrtizAlice LauRichard A HickmanFatima KhanFahad ParyaniAlice TangKenneth OforiEmily MiyoshiNeethu MichaelNicolette McClureXena E FlowersJean Paul VonsattelShawn DavidsonVilas MenonVivek SwarupErnest FraenkelJames E GoldmanLeslie M ThompsonPublished in: Nature communications (2022)
The complexity of affected brain regions and cell types is a challenge for Huntington's disease (HD) treatment. Here we use single nucleus RNA sequencing to investigate molecular pathology in the cortex and striatum from R6/2 mice and human HD post-mortem tissue. We identify cell type-specific and -agnostic signatures suggesting oligodendrocytes (OLs) and oligodendrocyte precursors (OPCs) are arrested in intermediate maturation states. OL-lineage regulators OLIG1 and OLIG2 are negatively correlated with CAG length in human OPCs, and ATACseq analysis of HD mouse NeuN-negative cells shows decreased accessibility regulated by OL maturation genes. The data implicates glucose and lipid metabolism in abnormal cell maturation and identify PRKCE and Thiamine Pyrophosphokinase 1 (TPK1) as central genes. Thiamine/biotin treatment of R6/1 HD mice to compensate for TPK1 dysregulation restores OL maturation and rescues neuronal pathology. Our insights into HD OL pathology spans multiple brain regions and link OL maturation deficits to abnormal thiamine metabolism.
Keyphrases
- single cell
- endothelial cells
- traumatic brain injury
- genome wide
- cell therapy
- resting state
- induced apoptosis
- gene expression
- multiple sclerosis
- cerebral ischemia
- functional connectivity
- stem cells
- induced pluripotent stem cells
- dna methylation
- mesenchymal stem cells
- adipose tissue
- machine learning
- blood pressure
- combination therapy
- mouse model
- oxidative stress
- signaling pathway
- electronic health record
- endoplasmic reticulum stress
- weight loss
- fatty acid
- bone marrow
- artificial intelligence
- data analysis