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

Ryan G. Lim(University of California, Irvine), Osama Al‐Dalahmah(Columbia University), Jie Wu(University of California, Irvine), Maxwell P. Gold(Massachusetts Institute of Technology), Jack C. Reidling(University of California, Irvine), Guomei Tang(Columbia University), Miriam Adam(Massachusetts Institute of Technology), David K. Dansu(The Graduate Center, CUNY), Hye-Jin Park(The Graduate Center, CUNY), Patrizia Casaccia(The Graduate Center, CUNY), Ricardo Miramontes(University of California, Irvine), Andrea M. Reyes-Ortiz(University of California, Irvine), Alice Lau(University of California, Irvine), Richard A. Hickman(Columbia University), Fatima Khan(Columbia University), Fahad Paryani(Columbia University), Alice Tang(Columbia University), Kenneth Ofori(Columbia University), Emily Miyoshi(University of California, Irvine), Neethu Michael(University of California, Irvine), Nicolette R. McClure(University of California, Irvine), Xena Flowers(Columbia University), Jean Paul Vonsattel(Columbia University), Shawn M. Davidson(Princeton University), Vilas Menon(Columbia University), Vivek Swarup(University of California, Irvine), Ernest Fraenkel(Massachusetts Institute of Technology), James E. Goldman(Columbia University Irving Medical Center), Leslie M. Thompson(University of California, Irvine)
Nature Communications
December 21, 2022
10.1038/s41467-022-35388-x
Cited by 75Open Access
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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.

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