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.

Here the authors evaluate single cell gene expression from mouse and human Huntington’s disease brains, finding incomplete oligodendrocyte maturation and pathways involved. Treating mice with thiamine/biotin ameliorates molecular pathology.

Details

Title
Huntington disease oligodendrocyte maturation deficits revealed by single-nucleus RNAseq are rescued by thiamine-biotin supplementation
Author
Lim, Ryan G. 1   VIAFID ORCID Logo  ; Al-Dalahmah, Osama 2   VIAFID ORCID Logo  ; Wu, Jie 3   VIAFID ORCID Logo  ; Gold, Maxwell P. 4 ; Reidling, Jack C. 1 ; Tang, Guomei 5   VIAFID ORCID Logo  ; Adam, Miriam 4 ; Dansu, David K. 6   VIAFID ORCID Logo  ; Park, Hye-Jin 6 ; Casaccia, Patrizia 6   VIAFID ORCID Logo  ; Miramontes, Ricardo 1 ; Reyes-Ortiz, Andrea M. 3 ; Lau, Alice 7 ; Hickman, Richard A. 2 ; Khan, Fatima 2 ; Paryani, Fahad 5 ; Tang, Alice 2 ; Ofori, Kenneth 2   VIAFID ORCID Logo  ; Miyoshi, Emily 8   VIAFID ORCID Logo  ; Michael, Neethu 9 ; McClure, Nicolette 8 ; Flowers, Xena E. 10 ; Vonsattel, Jean Paul 10 ; Davidson, Shawn 11 ; Menon, Vilas 5   VIAFID ORCID Logo  ; Swarup, Vivek 12   VIAFID ORCID Logo  ; Fraenkel, Ernest 4   VIAFID ORCID Logo  ; Goldman, James E. 10   VIAFID ORCID Logo  ; Thompson, Leslie M. 13   VIAFID ORCID Logo 

1  UCI MIND, University of California Irvine, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243) 
2  Columbia University Irving Medical Center, Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, New York, USA (GRID:grid.239585.0) (ISNI:0000 0001 2285 2675) 
3  University of California Irvine, Department of Biological Chemistry, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243) 
4  Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, USA (GRID:grid.116068.8) (ISNI:0000 0001 2341 2786) 
5  Columbia University Irving Medical Center, Department of Neurology, Vagelos College of Physicians and Surgeons, New York, USA (GRID:grid.239585.0) (ISNI:0000 0001 2285 2675) 
6  Advanced Science Research Center at the City University of New York, New York, USA (GRID:grid.212340.6) (ISNI:0000000122985718) 
7  University of California Irvine, Department of Psychiatry and Human Behavior, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243) 
8  University of California Irvine, Department of Neurobiology and Behavior, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243) 
9  University of California Irvine, Department of Pathology, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243) 
10  Columbia University Irving Medical Center, Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, New York, USA (GRID:grid.239585.0) (ISNI:0000 0001 2285 2675); Columbia University Irving Medical Center, New York City, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, New York, USA (GRID:grid.239585.0) (ISNI:0000 0001 2285 2675) 
11  Lewis-Sigler Institute for Integrative Genomics, Princeton, USA (GRID:grid.239585.0) 
12  UCI MIND, University of California Irvine, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243); University of California Irvine, Department of Neurobiology and Behavior, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243) 
13  UCI MIND, University of California Irvine, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243); University of California Irvine, Department of Biological Chemistry, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243); University of California Irvine, Department of Psychiatry and Human Behavior, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243); University of California Irvine, Department of Neurobiology and Behavior, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243); Sue and Bill Gross Stem Cell Center University of California Irvine, Irvine, USA (GRID:grid.266093.8) (ISNI:0000 0001 0668 7243) 
Pages
7791
Publication year
2022
Publication date
2022
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-022-35388-x
ProQuest document ID
2756507818
Copyright
© The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.