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Huntington disease oligodendrocyte maturation deficits revealed by single-nucleus RNAseq are rescued by thiamine-biotin supplementation.
Lim, Ryan G; Al-Dalahmah, Osama; Wu, Jie; Gold, Maxwell P; Reidling, Jack C; Tang, Guomei; Adam, Miriam; Dansu, David K; Park, Hye-Jin; Casaccia, Patrizia; Miramontes, Ricardo; Reyes-Ortiz, Andrea M; Lau, Alice; Hickman, Richard A; Khan, Fatima; Paryani, Fahad; Tang, Alice; Ofori, Kenneth; Miyoshi, Emily; Michael, Neethu; McClure, Nicolette; Flowers, Xena E; Vonsattel, Jean Paul; Davidson, Shawn; Menon, Vilas; Swarup, Vivek; Fraenkel, Ernest; Goldman, James E; Thompson, Leslie M.
Afiliación
  • Lim RG; UCI MIND, University of California Irvine, Irvine, CA, USA.
  • Al-Dalahmah O; Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
  • Wu J; Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA.
  • Gold MP; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Reidling JC; UCI MIND, University of California Irvine, Irvine, CA, USA.
  • Tang G; Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
  • Adam M; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Dansu DK; Advanced Science Research Center at the City University of New York, New York, NY, USA.
  • Park HJ; Advanced Science Research Center at the City University of New York, New York, NY, USA.
  • Casaccia P; Advanced Science Research Center at the City University of New York, New York, NY, USA.
  • Miramontes R; UCI MIND, University of California Irvine, Irvine, CA, USA.
  • Reyes-Ortiz AM; Department of Biological Chemistry, University of California Irvine, Irvine, CA, USA.
  • Lau A; Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA, USA.
  • Hickman RA; Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
  • Khan F; Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
  • Paryani F; Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
  • Tang A; Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
  • Ofori K; Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
  • Miyoshi E; Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, USA.
  • Michael N; Department of Pathology, University of California Irvine, Irvine, CA, USA.
  • McClure N; Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, USA.
  • Flowers XE; Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
  • Vonsattel JP; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York City, New York, NY, USA.
  • Davidson S; Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
  • Menon V; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York City, New York, NY, USA.
  • Swarup V; Lewis-Sigler Institute for Integrative Genomics, Princeton, NJ, USA.
  • Fraenkel E; Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
  • Goldman JE; UCI MIND, University of California Irvine, Irvine, CA, USA.
  • Thompson LM; Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, USA.
Nat Commun ; 13(1): 7791, 2022 12 21.
Article en En | MEDLINE | ID: mdl-36543778
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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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Tiamina / Biotina / Oligodendroglía / Enfermedad de Huntington Límite: Animals / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Tiamina / Biotina / Oligodendroglía / Enfermedad de Huntington Límite: Animals / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos