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

Author

Listed:
  • 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
    Columbia University Irving Medical Center, New York City)

  • Jean Paul Vonsattel

    (Columbia University Irving Medical Center
    Columbia University Irving Medical Center, New York City)

  • Shawn Davidson

    (Lewis-Sigler Institute for Integrative Genomics)

  • Vilas Menon

    (Columbia University Irving Medical Center)

  • Vivek Swarup

    (UCI MIND, University of California Irvine
    University of California Irvine)

  • Ernest Fraenkel

    (Department of Biological Engineering, Massachusetts Institute of Technology)

  • James E. Goldman

    (Columbia University Irving Medical Center
    Columbia University Irving Medical Center, New York City)

  • Leslie M. Thompson

    (UCI MIND, University of California Irvine
    University of California Irvine
    University of California Irvine
    University of California Irvine)

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.

Suggested Citation

  • 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-Ort, 2022. "Huntington disease oligodendrocyte maturation deficits revealed by single-nucleus RNAseq are rescued by thiamine-biotin supplementation," Nature Communications, Nature, vol. 13(1), pages 1-23, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35388-x
    DOI: 10.1038/s41467-022-35388-x
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