DPYD links glial lipids and myelination to sleep duration

Abstract

The regulation of sleep is heritable and conserved across species1,2, but the governing genetic mechanisms remain poorly understood. Here, we investigate the role of DPYD--which encodes the pyrimidine catabolic enzyme, dihydropyrimidine dehydrogenase--in sleep. Using a cross-species approach, we show that DPYD and its orthologs act specifically in glia to promote sleep through the regulation of brain lipids. In mouse and zebrafish, we find that DPYD orthologs are enriched in oligodendrocyte lineage cells, and their loss reduces myelination and sleep independent of DPYDs established role in uracil catabolism to {beta}-alanine. Genetic and pharmacological manipulations of myelin in zebrafish show that altering myelination is sufficient to perturb sleep duration. In Drosophila, which lack myelin, we find that the DPYD ortholog acts in ensheathing glia to promote sleep through formation of glial lipid droplets, a proposed evolutionary precursor to myelin. Furthermore, a human GWAS-identified sleep variant2 resides in a conserved cis-regulatory element that selectively contacts the promoter of DPYD within oligodendrocytes, connecting the human genetic association to oligodendrocyte-specific control of DPYD. Together, these results identify a deeply conserved role for glial lipids in sleep regulation and establish DPYD as a mechanistic link between myelin biology and sleep.

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BibTeX RIS

BibTeX

@misc{zimmerman2026dpyd,
  title = {{DPYD links glial lipids and myelination to sleep duration}},
  author = {A. J. Zimmerman and S. Deal and E. Almeraya Del Valle and J. Donnelly and F. Kroll and X. Guo and T. Tsundupalli and Z. Shetty and F. Doldur-Balli and B. Keenan and S. F. Grant and J. Rihel and A. Sehgal and A. I. Pack},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.31.763190},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.31.763190v1},
  note = {CC BY-ND},
}

RIS

TY  - UNPB
TI  - DPYD links glial lipids and myelination to sleep duration
AU  - A. J. Zimmerman
AU  - S. Deal
AU  - E. Almeraya Del Valle
AU  - J. Donnelly
AU  - F. Kroll
AU  - X. Guo
AU  - T. Tsundupalli
AU  - Z. Shetty
AU  - F. Doldur-Balli
AU  - B. Keenan
AU  - S. F. Grant
AU  - J. Rihel
AU  - A. Sehgal
AU  - A. I. Pack
PY  - 2026
DA  - 2026/10/31
PB  - bioRxiv
DO  - 10.64898/2026.10.31.763190
UR  - https://www.biorxiv.org/content/10.64898/2026.10.31.763190v1
AB  - The regulation of sleep is heritable and conserved across species1,2, but the governing genetic mechanisms remain poorly understood. Here, we investigate the role of DPYD--which encodes the pyrimidine catabolic enzyme, dihydropyrimidine dehydrogenase--in sleep. Using a cross-species approach, we show that DPYD and its orthologs act specifically in glia to promote sleep through the regulation of brain lipids. In mouse and zebrafish, we find that DPYD orthologs are enriched in oligodendrocyte lineage cells, and their loss reduces myelination and sleep independent of DPYDs established role in uracil catabolism to {beta}-alanine. Genetic and pharmacological manipulations of myelin in zebrafish show that altering myelination is sufficient to perturb sleep duration. In Drosophila, which lack myelin, we find that the DPYD ortholog acts in ensheathing glia to promote sleep through formation of glial lipid droplets, a proposed evolutionary precursor to myelin. Furthermore, a human GWAS-identified sleep variant2 resides in a conserved cis-regulatory element that selectively contacts the promoter of DPYD within oligodendrocytes, connecting the human genetic association to oligodendrocyte-specific control of DPYD. Together, these results identify a deeply conserved role for glial lipids in sleep regulation and establish DPYD as a mechanistic link between myelin biology and sleep.
ER  -

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