Huntington disease oligodendrocyte maturation deficits revealed by single-nucleus RNAseq are rescued by thiamine-biotin supplementation
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s41467-022-35388-x.pdf
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Published version
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5.06 MB
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Checksum (MD5)
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Author(s)
Lim, Ryan G
Al-Dalahmah, Osama
Wu, Jie
Gold, Maxwell P
Reidling, Jack C
Tang, Guomei
Adam, Miriam
Dansu, David K
Park, Hye-Jin
Casaccia, Patrizia
Date Issued
December 21, 2022
Journal
Nature Communications
Publisher
Springer Science and Business Media LLC
Citation
Lim, Ryan G, Al-Dalahmah, Osama, Wu, Jie, Gold, Maxwell P, Reidling, Jack C et al. 2022. "Huntington disease oligodendrocyte maturation deficits revealed by single-nucleus RNAseq are rescued by thiamine-biotin supplementation." Nature Communications, 13 (1).
Version
Final published version
Abstract
AbstractThe 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.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
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Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1038/s41467-022-35388-x
