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

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 MichaelNicolette McClure, Xena E. Flowers, Jean Paul Vonsattel, Shawn Davidson, Vilas Menon, Vivek Swarup, Ernest Fraenkel, James E. Goldman, Leslie M. Thompson

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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.

Original language	English
Article number	7791
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-35388-x
State	Published - Dec 2022
Externally published	Yes

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Lim, R. G., Al-Dalahmah, O., Wu, J., Gold, M. P., Reidling, J. C., Tang, G., Adam, M., Dansu, D. K., Park, H. J., Casaccia, P., Miramontes, R., Reyes-Ortiz, A. M., Lau, A., Hickman, R. A., Khan, F., Paryani, F., Tang, A., Ofori, K., Miyoshi, E., ... Thompson, L. M. (2022). Huntington disease oligodendrocyte maturation deficits revealed by single-nucleus RNAseq are rescued by thiamine-biotin supplementation. Nature Communications, 13(1), Article 7791. https://doi.org/10.1038/s41467-022-35388-x

@article{a85e6f650f3f411abb307d6cfdd4a39a,

title = "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{\textquoteright}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.",

author = "Lim, {Ryan G.} and Osama Al-Dalahmah and Jie Wu and Gold, {Maxwell P.} and Reidling, {Jack C.} and Guomei Tang and Miriam Adam and Dansu, {David K.} and Park, {Hye Jin} and Patrizia Casaccia and Ricardo Miramontes and Reyes-Ortiz, {Andrea M.} and Alice Lau and Hickman, {Richard A.} and Fatima Khan and Fahad Paryani and Alice Tang and Kenneth Ofori and Emily Miyoshi and Neethu Michael and Nicolette McClure and Flowers, {Xena E.} and Vonsattel, {Jean Paul} and Shawn Davidson and Vilas Menon and Vivek Swarup and Ernest Fraenkel and Goldman, {James E.} and Thompson, {Leslie M.}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41467-022-35388-x",

language = "English",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

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Lim, RG, Al-Dalahmah, O, Wu, J, Gold, MP, Reidling, JC, Tang, G, Adam, M, Dansu, DK, Park, HJ, Casaccia, P, Miramontes, R, Reyes-Ortiz, AM, Lau, A, Hickman, RA, Khan, F, Paryani, F, Tang, A, Ofori, K, Miyoshi, E, Michael, N, McClure, N, Flowers, XE, Vonsattel, JP, Davidson, S, Menon, V, Swarup, V, Fraenkel, E, Goldman, JE & Thompson, LM 2022, 'Huntington disease oligodendrocyte maturation deficits revealed by single-nucleus RNAseq are rescued by thiamine-biotin supplementation', Nature Communications, vol. 13, no. 1, 7791. https://doi.org/10.1038/s41467-022-35388-x

TY - JOUR

T1 - Huntington disease oligodendrocyte maturation deficits revealed by single-nucleus RNAseq are rescued by thiamine-biotin supplementation

AU - Lim, Ryan G.

AU - Al-Dalahmah, Osama

AU - Wu, Jie

AU - Gold, Maxwell P.

AU - Reidling, Jack C.

AU - Tang, Guomei

AU - Adam, Miriam

AU - Dansu, David K.

AU - Park, Hye Jin

AU - Casaccia, Patrizia

AU - Miramontes, Ricardo

AU - Reyes-Ortiz, Andrea M.

AU - Lau, Alice

AU - Hickman, Richard A.

AU - Khan, Fatima

AU - Paryani, Fahad

AU - Tang, Alice

AU - Ofori, Kenneth

AU - Miyoshi, Emily

AU - Michael, Neethu

AU - McClure, Nicolette

AU - Flowers, Xena E.

AU - Vonsattel, Jean Paul

AU - Davidson, Shawn

AU - Menon, Vilas

AU - Swarup, Vivek

AU - Fraenkel, Ernest

AU - Goldman, James E.

AU - Thompson, Leslie M.

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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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U2 - 10.1038/s41467-022-35388-x

DO - 10.1038/s41467-022-35388-x

M3 - Article

C2 - 36543778

AN - SCOPUS:85144559555

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 7791

ER -

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

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