Dataset Information

Loss of ribosomal RNA methyltransferase Nsun5 Leads to Hypomyelination and Reduced Sleep Amount

ABSTRACT: Sleep is regulated by intricate homeostatic and circadian systems and is influenced by genetic, environmental, and lifestyle factors. However, the roles of the epitranscriptome in sleep-wake regulation remain to be clarified. Here, we find that mice lacking the rRNA methyltransferase Nsun5 exhibit prolonged wakefulness. The absence of Nsun5 decreases 28S rRNA m5C levels, impairing the translational efficiency of nascent proteins associated with myelination, microtubule-based movement, and ribosome binding. This leads to a decreased number of oligodendrocytes and hypomyelination. These deficits result in increased excitability, particularly within the cortex. Notably, restoring myelination properties with clemastine or blocking the abnormally exposed voltage-gated potassium channels rescues the sleep phenotype, suggesting that reduced sleep is associated with hypomyelination. These findings highlight the significant role of epigenetic modifications in sleep regulation and offer broad mechanistic and therapeutic implications for brain disorders involving both myelin and sleep disturbances.

ORGANISM(S): Mus Musculus

SUBMITTER: Zhili Huang

PROVIDER: PXD054359 | iProX | Mon Jul 29 00:00:00 BST 2024

REPOSITORIES: iProX

ACCESS DATA

Similar Datasets

Project description:Objective The objective of the current trial is to investigate the effect of perioperative sleep and circadian rhythm on the natural course of survival among patient diagnosed with colorectal cancer. Concurrently, outcome measures like depression, fatigue, quality of life, and co-morbidity will be measured continuously in the short-, intermediate- and long-term period following diagnosis. The a-priori hypothesis is that preoperative sleep and circadian disturbances is a prognostic marker of reduced overall survival. Likewise, preoperative sleep-wake disturbances at baseline are expected to result in overall universally reduced quality of life, increased depression and fatigue. Furthermore, development of sleep-wake disturbances in the postoperative period as compared to preoperative sleep-wake rhythm is expected to a prognostic marker of negative outcomes. Target and study population The study population are all patients diagnosed with colorectal cancer in Region Zealand recruited consecutively from the trial initiation until study end each patient with an intended 5 year follow-up period. All available cases will be included in the trial. Study design The study will be an observational prospective cohort study applying a longituditional repeated measure design. Exposures and outcomes of interest The primary outcomes in the trial are sleep and circadian outcomes measured via actigraphy in the perioperative period. Furthermore, cancer related survival and overall survival in the 5 year follow-up period is considered primary outcomes. Secondary outcomes consist of consecutively measured depression, fatigue, quality of life, follow-up treatment and co-morbidity. Exposure variables are primary related to the cancer, i.e. cancer stage, surgical treatment, oncological treatment, baseline co-morbidity and pharmacological treatment. Some of the secondary outcomes could be expected to serve as confounding or mediating factors. Meaningful control for confounding will in the analysis phase be cancer stage and baseline sleep-wake rhythm status. Sampling methods All available cases will be sought included in the trial. No formal sample size has been performed and continues inclusion into the trial will be performed during an 1,5 year period. Statistical analyses The relationship between overall survival and baseline sleep-wake rhythm will be investigated using survival statistics and/or multivariate logistic regression. Expected results The investigators expect to see a marked difference in overall survival among patients with sleep and circadian disturbances at baseline.

Project description:Extended periods of waking result in physiological impairments in humans, rats, and flies. Sleep homeostasis, the increase in sleep observed following sleep loss, is believed to counter the negative effects of prolonged waking by restoring vital biological processes that are degraded during sleep deprivation. Sleep homeostasis, as with other behaviors, is influenced by both genes and environment. We report here that during periods of starvation, flies remain spontaneously awake but, in contrast to sleep deprivation, do not accrue any of the negative consequences of prolonged waking. Specifically, the homeostatic response and learning impairments that are a characteristic of sleep loss are not observed following prolonged waking induced by starvation. To identify the genes responsible for the protective effects of starvation we conducted transcription profiling of sleep deprived flies that accrue sleep debt compared to starved siblings that do not. Genes involved in lipid metabolism were highly enriched in our dataset of 84 differentially regulated transcripts. Follow up genetic studies established that 6 genes involved in lipid metabolism strongly influence sleep homeostasis. Two of these genes, brummer (bmm) and Lipid storage droplet 2 (Lsd2), are in the same lipolysis pathway but exert antagonistic effects on lipid storage. bmm mutant flies have excess fat stores and display a large homeostatic response following sleep deprivation. In contrast, Lsd2 mutant flies, which phenocopy aspects of starvation as measured by low triglyceride stores, do not exhibit a homeostatic response following sleep loss. Importantly, Lsd2 mutant flies are not learning impaired after sleep deprivation. These results provide the first genetic evidence, to our knowledge, that lipid metabolism plays an important role in regulating the homeostatic response and can protect against neuronal impairments induced by prolonged waking. Two-condition experiments: sleep deprived vs starved. RNA from 8 biological replicates for each condition was pooled in groups of 2 to create 4 samples. Each of the 4 samples is run in duplicate with untreated circadian matched controls.

Project description:Background: Age-related cognitive deficits negatively affect quality of life and can presage serious neurodegenerative disorders. Despite sleep disruption’s well-recognized negative influence on cognition, and its prevalence with age, surprisingly few studies have tested sleep’s relationship to cognitive aging. Methodology: We measured sleep stages in young adult and aged F344 rats during inactive (enhanced sleep) and active (enhanced wake) periods. Animals were behaviorally characterized on the Morris water maze and gene expression profiles of their parietal cortices were taken. Principal Findings: Water maze performance was impaired, and inactive period deep sleep was decreased with age. However, increased deep sleep during the active period was most strongly correlated to maze performance. Transcriptional profiles were strongly associated with behavior and age, and were validated against prior studies. Bioinformatic analysis revealed increased translation and decreased myelin/ neuronal pathways. Conclusions: The F344 rat appears to serve as a reasonable model for some common sleep architecture and cognitive changes seen with age in humans, including the cognitively disrupting influence of active period deep sleep. Microarray analysis suggests that the processes engaged by this sleep are consistent with its function. Thus, active period deep sleep appears temporally misaligned but mechanistically intact, leading to the following: first, aged brain tissue appears capable of generating the slow waves necessary for deep sleep, albeit at a weaker intensity than in young. Second, this activity, presented during the active period, seems disruptive rather than beneficial to cognition. Third, this active period deep sleep may be a cognitively pathologic attempt to recover age-related loss of inactive period deep sleep. Finally, therapeutic strategies aimed at reducing active period deep sleep (e.g., by promoting active period wakefulness and/or inactive period deep sleep) may be highly relevant to cognitive function in the aging community. KEYWORDS: frontal cortex, rat, young or aged We implanted young and aged Fischer 344 rats (n = 6/ group) with wireless EEG, EMG and movement monitoring devices to measure sleep architecture. Animals were trained in the Morris water maze to assess cognitive function, and frontal cortices were removed for microarray analysis.sleep disruption and cognitive decline.

Dataset Information

Loss of ribosomal RNA methyltransferase Nsun5 Leads to Hypomyelination and Reduced Sleep Amount

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure