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

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.

SUBMITTER: Lim RG

PROVIDER: S-EPMC9772349 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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

Lim Ryan G RG Al-Dalahmah Osama O Wu Jie J Gold Maxwell P MP Reidling Jack C JC Tang Guomei G Adam Miriam M Dansu David K DK Park Hye-Jin HJ Casaccia Patrizia P Miramontes Ricardo R Reyes-Ortiz Andrea M AM Lau Alice A Hickman Richard A RA Khan Fatima F Paryani Fahad F Tang Alice A Ofori Kenneth K Miyoshi Emily E Michael Neethu N McClure Nicolette N Flowers Xena E XE Vonsattel Jean Paul JP Davidson Shawn S Menon Vilas V Swarup Vivek V Fraenkel Ernest E Goldman James E JE Thompson Leslie M LM

Nature communications 20221221 1

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 correla ...[more]

PMID: 36543778

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Project description:IntroductionBiotin-thiamine responsive basal ganglia disease (BTBGD) is a rare autosomal recessive neurometabolic disorder characterized by diverse and variable phenotypic features, which can make diagnosis challenging. However, prompt treatment with thiamine and biotin can effectively manage the condition. Diagnosis relies on the identification of biallelic pathogenic variants in the SLC19A3 gene. This case report describes two novel variants of uncertain significance in the SLC19A3 gene, which may be correlated with the phenotypic manifestations of BTBGD.Case presentationOur case is a 7-month-old female infant who presented with a 3-week history of irritability, altered behavior, and refusal of newly introduced solid foods. Symptoms started with an upper respiratory tract infection, followed by lethargy, floppiness, and abnormal movements. The patient was admitted to the pediatric ward with a broad differential diagnosis. Extensive laboratory evaluations revealed lactic acidosis. MRI brain showed symmetric restricted diffusion affecting the bilateral basal ganglia, thalami, and cortical regions. Whole genome sequencing identified biallelic variants of the SLC19A3: a c.1364T>G p.Met455Arg missense variant in the maternal allele and a 2.3 kb deletion of intron 3 of the paternal allele. Both variants were identified as variants of uncertain significance. However, given the clinical picture, MRI brain findings, resolution of symptoms with empiric biotin and thiamine supplementation, and biallelic SLC19A3 variants of unknown significance, the patient most likely suffers from BTBGD. Patient continues to show sustained developmental progress on biotin and thiamine supplementation.ConclusionThis case highlights the fact that genetic testing remains a vital but improvable tool for the diagnosis of BTBGD. As of yet, genetic testing and diagnosis of BTBGD continues to be limited by the knowledge of which SLC19A3 variants are established to be pathogenic variants. Thus, further research is required to study other SCL19A3 variants of unknown significance to further improve genetic testing and diagnosis of BTBGD in the future.

Project description:Thiamine prevents diabetic complications, and its deficiency, resulting from mutation of thiamine transporter gene SLC19A2 has been linked to diabetes mellitus. We previously found that thiamine mitigates metabolic disorders in spontaneous hypertensive rats, harboring defects in glucose and fatty acid metabolism. The current study extends our hypothesis that that thiamine intervention may impact metabolic abnormalities in polyphagia-induced Otsuka Long-Evans Tokushima Fatty (OLETF) rats that lack functional cholecystokinin A receptors. Male OLETF rats exhibit progressive obesity and metabolic disorders similar to human metabolic syndrome. Male OLETF rats (4-week-old) were given free access to water containing either 0.2 % or 0 % of thiamine for 51 weeks. At the end of treatment, blood parameters and cardiac functions were analyzed. After sacrifice, the organs were removed and weights of organs and histological findings were evaluated. In addition, differential gene expression in the liver was analyzed. Thiamine intervention averted obesity, mainly resulting from reduction of visceral adiposity, and prevented metabolic disorders in OLETF rats. Histological evaluation revealed that thiamine alleviated adipocyte hypertrophy, steatosis in the liver, heart, and skeletal muscle, interstitial fibrosis in the heart and kidney, fatty degeneration in the pancreas, thickening of the basement membrane of vasculature, and glomerulopathy and mononuclear cell infiltration in the kidney. Cardiac and renal functions were preserved in thiamine treatment. Seventy-six genes showed at least two-fold difference in hepatic expression with thiamine treatment. Several of them participated in carbohydrate metabolism (Hk1, Pygb, Slc2a8, Rtn4, Rhbdl1, and Tspan8), lipid metabolism (Pla2g15, Por, and Lmf1), vascular physiology (S1pr1, Epha8, Rtn4, Slc7a13, Cdh15, Itga9, Cd151, Cd40lg, Nid1 and Lamb1), and carcinogenesis (Lmo7, Fgfr3, and Dmbt1). Modification of transcript expression well accorded with the findings of blood parameters and organ morphologies. Thiamine prevented polyphagia-induced obesity and metabolic and functional disorders in OLETF rats.

Dataset Information

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

Publications

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

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