Huntington disease oligodendrocyte maturation deficits revealed by single-nucleus RNAseq are rescued by thiamine-biotin supplementation

Ryan G. Lim, Osama Al-Dalahmah, Jie Wu, Maxwell P. Gold, Jack C. Reidling, Guomei Tang, Miriam Adam, David K. Dansu, Hye-Jin Park, Patrizia Casaccia, Ricardo Miramontes, Andrea M. Reyes-Ortiz, Alice Lau, Richard A. Hickman, Fatima Khan, Fahad Paryani, Alice Tang, Kenneth Ofori, Emily Miyoshi, Neethu Michael, Nicolette McClure, Xena E. Flowers, Jean Paul Vonsattel, Shawn Davidson, Vilas Menon, Vivek Swarup, Ernest Fraenkel, James E. Goldman () and Leslie M. Thompson ()
Additional contact information
Ryan G. Lim: UCI MIND, University of California Irvine
Osama Al-Dalahmah: Columbia University Irving Medical Center
Jie Wu: University of California Irvine
Maxwell P. Gold: Department of Biological Engineering, Massachusetts Institute of Technology
Jack C. Reidling: UCI MIND, University of California Irvine
Guomei Tang: Columbia University Irving Medical Center
Miriam Adam: Department of Biological Engineering, Massachusetts Institute of Technology
David K. Dansu: Advanced Science Research Center at the City University of New York
Hye-Jin Park: Advanced Science Research Center at the City University of New York
Patrizia Casaccia: Advanced Science Research Center at the City University of New York
Ricardo Miramontes: UCI MIND, University of California Irvine
Andrea M. Reyes-Ortiz: University of California Irvine
Alice Lau: University of California Irvine
Richard A. Hickman: Columbia University Irving Medical Center
Fatima Khan: Columbia University Irving Medical Center
Fahad Paryani: Columbia University Irving Medical Center
Alice Tang: Columbia University Irving Medical Center
Kenneth Ofori: Columbia University Irving Medical Center
Emily Miyoshi: University of California Irvine
Neethu Michael: University of California Irvine
Nicolette McClure: University of California Irvine
Xena E. Flowers: Columbia University Irving Medical Center
Jean Paul Vonsattel: Columbia University Irving Medical Center
Shawn Davidson: Lewis-Sigler Institute for Integrative Genomics
Vilas Menon: Columbia University Irving Medical Center
Vivek Swarup: UCI MIND, University of California Irvine
Ernest Fraenkel: Department of Biological Engineering, Massachusetts Institute of Technology
James E. Goldman: Columbia University Irving Medical Center
Leslie M. Thompson: UCI MIND, University of California Irvine

Nature Communications, 2022, vol. 13, issue 1, 1-23

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-35388-x

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