DPYD links glial lipids and myelination to sleep duration
Authors: A. J. Zimmerman, S. Deal, E. Almeraya Del Valle, J. Donnelly, F. Kroll, X. Guo, T. Tsundupalli, Z. Shetty, F. Doldur-Balli, B. Keenan, S. F. Grant, J. Rihel, A. Sehgal, A. I. Pack
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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Developmental sleep during lethargus is associated with metabolic homeostasis and heritable adaptive responses to infection in Caenorhabditis elegans.Bynedi Sheshatri Chinna Mounish, Kannan Srilekha, Ramesh Anand et al. · 2026 · Biochemical and Biophysical Research Communications - BBRC · Not summarized yet
The study disrupts developmental sleep in C. elegans and measures metabolic consequences, including lipid changes, rather than testing DPYD or glial myelination.
Abstract
Sleep is a fundamental physiological state essential for metabolic and neuronal homeostasis; however, its contribution to lipid and energy metabolism during development remains incompletely understood. Here, we used Caenorhabditis elegans to investigate the metabolic significance of Developmentally Timed Sleep (DTS). Lethargus-associated DTS was mechanically disrupted using 1 kHz piezoelectric buzzer-induced mechanical stimulation, followed by behavioural, physiological, metabolic and molecular analyses. DTS disruption was associated with reduced behavioural quiescence, altered sleep-associated gene expression, reduced survival and elevated oxidative stress. Notably, disruption during the L4…
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The study examines sleep consolidation through cholinergic neurons in a Drosophila neurofibromatosis model, not glial lipid regulation.
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A novel function of neuroligin 3 : Beyond sociality, Regulating lifespan in DrosophilaJ. Kurbaj, R. Ataei, AF Simon · 2026 · bioRxiv · preprint, not peer reviewed · Not summarized yet
The study examines Drosophila neuroligin 3 effects on sleep, social behavior, and lifespan rather than DPYD’s glial role.
Abstract
Neuroligins are conserved postsynaptic adhesion proteins involved in synaptic function and behaviour. In Drosophila melanogaster, Neuroligin 3 (Nlg3) regulates social behaviour, sleep and synaptic architecture. We now report, through analysis of publicly available transcriptomics data, confirmed with RT-qPCR data, that loss-of-function of the nlg3 gene downregulates the expression of longevity-associated genes foxo, hsp70s, and hsp68. Graded genetic manipulation of the Drosophila melanogaster neuroligin 3 (nlg3) gene indeed modulates both social spacing and lifespan. Specifically, reduced nlg3 expression (via heterozygous deletion, or transposable-element insertion) extends lifespan in both …
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The study discusses links between sleep disorders and glymphatic waste clearance, rather than sleep regulation by glial lipids or myelin.
Abstract
The glymphatic system, first described in 2012 by Iliff and Nedergaard's team, is a macroscopic waste clearance pathway in the central nervous system, and plays an essential role in maintaining brain homeostasis by facilitating the convective exchange of cerebrospinal fluid (CSF) with interstitial fluid (ISF) to remove neurotoxic solutes. Its functionality is inseparably linked to the physiological state of sleep, with clearance rates dramatically upregulated during non-rapid eye movement (NREM) sleep. Conversely, sleep disturbances, including sleep fragmentation, chronic insomnia, and obstructive sleep apnea (OSA), impair glymphatic function, leading to the accumulation of neurotoxic protei…
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The review surveys sleep and circadian effects on neuronal genome stability and retrotransposons, not DPYD-mediated glial lipid regulation.
Abstract
Sleep and wake are fundamental brain states that coordinate diverse physiological processes required for long-term health and survival. Recent research in molecular neuroscience and chronobiology has begun to clarify how sleep–wake cycles and circadian timing intersect with genomic maintenance mechanisms in the nervous system. In this Review, we summarize current evidence that sleep and circadian rhythms temporally regulate neuronal genome stability, with a particular focus on how they modulate neuronal retrotransposon activity. We discuss circadian clock-dependent regulation of DNA repair pathways, the contribution of sleep to chromosomal integrity and chromosome dynamics, and emerging data…
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The human-specific gene FRMPD2B couples postnatal experience to the expansion of cortical connectivityE. Christopoulou, J. Zamith, P. Bonadonna et al. · 2026 · bioRxiv preprint · AI summary available
In short
The paper identifies FRMPD2B as an experience- and activity-regulated human-specific gene that supports complex cortical neuron morphology and connectivity.
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The study tests how the Drosophila Insomniac protein affects seizures and ketogenic-diet response, rather than sleep duration or myelination.
Abstract
Background/Objectives: The ubiquitin proteasome system (UPS) serves critical cellular homeostatic functions that contribute to neurological health, including neuronal metabolism, synaptic plasticity, and the molecular circadian clock. The UPS is tightly regulated to ensure the correct balance of healthy proteins and those targeted for degradation and recycling; malfunction in this quality control process can contribute to disease states such as neurodegeneration and cancer. Target specificity in this system is due in part to ubiquitin ligase adaptor proteins, such as those of the BTB superfamily of proteins, which connect substrates to the larger proteasomal complex. In Drosophila, the BTB f…
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Glial Dysfunction and Memory Impairments in a Model of Pediatric Obstructive Sleep ApneaMichael R. Williamson, Jorge Botas, Mahyar J. Hedayatpour et al. · 2026 · Glia · Not summarized yet
The study examines glial dysfunction in a mouse model of pediatric sleep apnea, focusing on memory impairment rather than glial control of sleep.
Abstract
Pediatric obstructive sleep apnea (POSA) is a common childhood disease that often causes aberrant brain development and cognitive deficits. The pathophysiological underpinnings of cognitive impairments in POSA remain unclear. Here, we examined cellular and molecular aspects of pathology in a mouse model of POSA that features learning and memory deficits. We performed single‐nucleus RNA‐sequencing (snRNA‐seq) of the hippocampus to examine gene expression changes in an unbiased and cell type‐specific manner. This dataset revealed a striking perturbation of transcriptomes across all brain cell types, particularly within glia and neural stem cells. We validated reduced expression of several diff…
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