Single nuclei RNAseq analysis of HD mouse models and human brain reveals impaired oligodendrocyte maturation and potential role for thiamine metabolism
Lim, R. G.; Al-Dalahmah, O.; Wu, J. M.; Gold, M. P.; Reidling, J. C.; Tang, G.; Adam, M.; Dansu, D. K.; Park, H.-J.; Casaccia, P.; Miramontes, R.; Reyes-Ortiz, A. M.; Lau, A.; Khan, F.; Paryani, F.; Tang, A.; Ofori, K. N. A.; Miyoshi, E.; Michael, N.; Geller, N.; Flowers, X. E.; Vonsattel, J. P.; Davidson, S.; Menon, V.; Swarup, V.; Fraenkel, E.; Goldman, J. E.; Thompson, L. M.
Show abstract
The complexity of affected brain regions and cell types is a challenge for Huntingtons disease (HD) treatment. Here we used single nucleus RNA sequencing (snRNAseq) to investigate mechanism of pathology in the cortex and striatum from R6/2 mice at 8 and 12w and in three regions of human HD post-mortem tissue. We identified cell type-specific and cell agnostic signatures and found changes suggesting oligodendrocytes (OLs) and oligodendrocyte precursors (OPCs) were arrested in intermediate maturation states. OL-lineage regulators OLIG1 and OLIG2 were negatively correlated with CAG length in human OPCs, and ATACseq analysis of HD mouse NeuN-negative cells showed decreased accessibility of sites regulated by OL maturation genes. Glucose and lipid metabolism were implicated in abnormal cell maturation and PRKCE and Thiamine Pyrophosphokinase 1 were identified as central genes. High dose thiamine/biotin treatment of R6/1 HD mice to target thiamine metabolism not only restored OL maturation, but also rescued pathology in neurons. These findings reveal insights into HD OL pathology that spans multiple brain regions and link OL maturation deficits to abnormal thiamine metabolism.
Matching journals
The top 7 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- A topographical atlas of alpha-Synuclein dosage and cell-type expression in the mouse brain and periphery 95%
- Parkin is not required to sustain OXPHOS function in adult mammalian tissues 95%
- Epigenetic insights into neuropsychiatric and cognitive symptoms in Parkinson's disease: A DNA co-methylation network analysis 95%
Similar papers in this journal
- Molecular and spatial transcriptomic classification of midbrain dopamine neurons and their alterations in a LRRK2G2019S model of Parkinson's disease 97%
- Steady-state neuron-predominant LINE-1 encoded ORF1p protein and LINE-1 RNA increase with aging in the mouse and human brain 96%
- Transcriptional and epigenetic characterization of early striosomes identifies Foxf2 and Olig2 as factors required for development of striatal compartmentation and neuronal phenotypic differentiation 96%
Similar papers in this journal
- Single cell spatial transcriptomic and translatomic profiling of dopaminergic neurons in health, aging and disease 97%
- ALS molecular subtypes are a combination of cellular, genetic, and pathological features learned by deep multiomics classifiers 95%
- Hypoxia-inducible factor 1 protects neurons from Sarm1-mediated neurodegeneration 95%
Similar papers in this journal
- Intersecting impact of CAG repeat and Huntingtin knockout in stem cell-derived cortical neurons 98%
- Regional interneuron transcriptional changes reveal pathologic markers of disease progression in a mouse model of Alzheimer's disease 95%
- SARM1 activation induces reversible mitochondrial dysfunction and can be prevented in human neurons by antisense oligonucleotides 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.