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

• DOI: 10.1038/s41467-022-35388-x
• Publication Date: 2022-12-21T11:03:00Z
• Authors: 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-O...; 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
• Keywords: NeuN; OLIG2

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 striatum from R6/2 mice human HD post-mortem tissue. We identify type-specific -agnostic signatures suggesting oligodendrocytes (OLs) oligodendrocyte precursors (OPCs) are arrested intermediate maturation states. OL-lineage regulators OLIG1 OLIG2 negatively correlated with CAG length OPCs, ATACseq analysis mouse NeuN-negative cells shows decreased accessibility regulated by OL genes. data implicates glucose lipid metabolism abnormal PRKCE Thiamine Pyrophosphokinase 1 ( TPK1 ) as central Thiamine/biotin treatment R6/1 compensate dysregulation restores rescues neuronal pathology. Our insights into spans multiple link deficits thiamine metabolism.