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; Leslie M Thompson

doi:10.1038/s41467-022-35388-x

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

Nat Commun. 2022 Dec 21;13(1):7791. doi: 10.1038/s41467-022-35388-x.

Authors

Ryan G Lim^#¹, Osama Al-Dalahmah^#², Jie Wu^#³, Maxwell P Gold⁴, Jack C Reidling¹, Guomei Tang⁵, Miriam Adam⁴, David K Dansu⁶, Hye-Jin Park⁶, Patrizia Casaccia⁶, Ricardo Miramontes¹, Andrea M Reyes-Ortiz³, Alice Lau⁷, Richard A Hickman², Fatima Khan², Fahad Paryani⁵, Alice Tang², Kenneth Ofori², Emily Miyoshi⁸, Neethu Michael⁹, Nicolette McClure⁸, Xena E Flowers^{2

10}, Jean Paul Vonsattel^{2

10}, Shawn Davidson¹¹, Vilas Menon⁵, Vivek Swarup^{1

8}, Ernest Fraenkel⁴, James E Goldman^{12

13}, Leslie M Thompson^{14

15

16

17

18}

Affiliations

¹ UCI MIND, University of California Irvine, Irvine, CA, USA.
² Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
³ Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA.
⁴ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁵ Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
⁶ Advanced Science Research Center at the City University of New York, New York, NY, USA.
⁷ Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA, USA.
⁸ Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, USA.
⁹ Department of Pathology, University of California Irvine, Irvine, CA, USA.
¹⁰ Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York City, New York, NY, USA.
¹¹ Lewis-Sigler Institute for Integrative Genomics, Princeton, NJ, USA.
¹² Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA. jeg5@cumc.columbia.edu.
¹³ Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York City, New York, NY, USA. jeg5@cumc.columbia.edu.
¹⁴ UCI MIND, University of California Irvine, Irvine, CA, USA. lmthomps@hs.uci.edu.
¹⁵ Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA. lmthomps@hs.uci.edu.
¹⁶ Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA, USA. lmthomps@hs.uci.edu.
¹⁷ Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, USA. lmthomps@hs.uci.edu.
¹⁸ Sue and Bill Gross Stem Cell Center University of California Irvine, Irvine, CA, USA. lmthomps@hs.uci.edu.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Biotin* / metabolism
Biotin* / pharmacology
Dietary Supplements
Disease Models, Animal
Humans
Huntington Disease* / metabolism
Mice
Mice, Transgenic
Nerve Tissue Proteins / metabolism
Oligodendroglia* / metabolism
Solitary Nucleus / metabolism
Thiamine* / metabolism
Thiamine* / pharmacology

Substances

Biotin
Nerve Tissue Proteins
Thiamine

Abstract

Publication types

MeSH terms

Substances

Grants and funding