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
- genome wide
- traumatic brain injury
- cell therapy
- induced apoptosis
- induced pluripotent stem cells
- stem cells
- high fat diet induced
- dna methylation
- resting state
- combination therapy
- signaling pathway
- multiple sclerosis
- blood glucose
- transcription factor
- single molecule
- mesenchymal stem cells
- pluripotent stem cells
- cell proliferation
- weight loss
- big data
- mouse model
- genome wide identification
- machine learning
- bioinformatics analysis
- brain injury
- artificial intelligence
- endoplasmic reticulum stress
- prefrontal cortex
- wild type
- genome wide analysis