---
title: "Neurofibromin dNf1 Controls Sleep Consolidation Through Cholinergic Neurons in Drosophila"
id: "biorxiv-6-neurofibromin-regulates-sleep-consolidation-via-cholinergic-neurons-in-a"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-6-neurofibromin-regulates-sleep-consolidation-via-cholinergic-neurons-in-a"
content_type: "clinical_feed_article"
specialty: "Neurology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.10.20.760518v1?rss=1"
published_at: "2026-10-24T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Neurofibromin dNf1 Controls Sleep Consolidation Through Cholinergic Neurons in Drosophila
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-6-neurofibromin-regulates-sleep-consolidation-via-cholinergic-neurons-in-a
- **Specialty:** [Neurology](https://medichelpline.com/clinical-feed/neurology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.10.20.760518v1?rss=1)
- **Published At:** 2026-10-24T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- Investigators used Drosophila to model sleep phenotypes associated with **Neurofibromatosis 1** and examined the role of the NF1 ortholog **dNf1**. - Null dNf1 mutants displayed markedly reduced total sleep, with fewer and shorter nighttime sleep bouts and increased activity between bouts, reproducing human fragmented-sleep features. - Pan-neuronal RNAi knockdown reproduced the recessive sleep fragmentation phenotype; independent null alleles yielded similar deficits. - The research team mapped dNf1 expression broadly across the adult fly CNS (mushroom bodies, ellipsoid body, dorsal fan-shaped body, GABAergic neurons), but cell-type-restricted knockdown showed those populations were dispensable for sleep regulation. - Cell-restricted loss in **cholinergic neurons** alone was sufficient to reproduce the mutant sleep phenotype; restoring wild-type dNf1 to cholinergic neurons in nulls was necessary and sufficient for rescue. - Expression of the GAP-related domain (GRD) in cholinergic neurons normalized elevated **Ras/MAPK** signaling and fully restored sleep; a catalytically dead GRD variant failed to rescue, implicating Ras/MAPK dysregulation as the proximate mechanism. - Two disease-associated missense variants, dNf1C1045Y and dNf1R1861C, produced distinct, dose-graded sleep deficits: C1045Y resembled null and behaved like a dominant-negative in some contexts, while R1861C yielded milder, partially GRD-independent effects. - Authors note mutation-specific mechanisms that parallel clinical heterogeneity in NF1; the preprint did not report detailed electrophysiological correlates or behavioral rescue timelines and remains unreviewed.
## Clinical Analysis & Structured Key Points
Neurofibromin Regulates Sleep Consolidation via Cholinergic Neurons in a Drosophila Model of Neurofibromatosis 1 | bioRxiv Skip to main content New Results Neurofibromin Regulates Sleep Consolidation via Cholinergic Neurons in a Drosophila Model of Neurofibromatosis 1 View ORCID Profile Kalliopi Atsoniou , View ORCID Profile Eirini-Maria Georganta , View ORCID Profile Kathrin Pfeifer , View ORCID Profile Ruth Palmer , View ORCID Profile Martina Samiotaki , View ORCID Profile Efthimios MC Skoulakis doi: https://doi.org/10.64898/2026.10.20.760518 Kalliopi Atsoniou 1 Biomedical Sciences Research Center Alexander Fleming, Vari 16672, Greece; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Kalliopi Atsoniou Eirini-Maria Georganta 2 Biomedical Sciences Research Center Alexander Fleming, Vari 16672 Greece; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Eirini-Maria Georganta Kathrin Pfeifer 3 3. Dept of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Kathrin Pfeifer Ruth Palmer 4 Dept of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Ruth Palmer Martina Samiotaki 5 Biomedical Sciences Research Center Alexander Fleming, Vari 16672 Greece Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Martina Samiotaki Efthimios MC Skoulakis 1 Biomedical Sciences Research Center Alexander Fleming, Vari 16672, Greece; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Efthimios MC Skoulakis For correspondence: skoulakis{at}fleming.gr Abstract Info/History Metrics Supplementary material Preview PDF Abstract Neurofibromatosis type 1 (NF1) patients frequently present with fragmented, poor-quality sleep, but the neural circuits and molecular mechanisms underlying this deficit remain undefined. Using Drosophila, we show that loss of the NF1 ortholog dNf1 recapitulates the human phenotype: null mutants exhibit markedly reduced total sleep with blunted nighttime consolidation, reflected in fewer and shorter sleep bouts and elevated inter-bout activity, a recessive phenotype reproduced by independent null alleles and by pan-neuronal RNAi knockdown. Despite the broad expression of dNf1 across the adult CNS, including the mushroom bodies, ellipsoid body, dorsal fan-shaped body, and GABAergic neurons, cell-type-restricted knockdown showed the protein is dispensable for sleep regulation in each of these populations. Instead, dNf1 loss specifically in cholinergic neurons, the most abundant neuronal class in the fly brain, was sufficient to reproduce the deficient, fragmented sleep of null mutants, and restoring wild-type dNf1 to cholinergic neurons of null animals was both necessary and sufficient to rescue sleep. Mechanistically, cholinergic expression of the GAP-related domain (GRD) alone, which normalizes elevated Ras/MAPK signaling, fully restored sleep in nulls, whereas a catalytically dead GRD variant did not, establishing Ras/MAPK dysregulation in cholinergic neurons as the proximate cause. Two disease-associated missense mutations, dNf1C1045Y and dNf1R1861C, produced distinct, dose-graded sleep phenotypes. dNf1C1045Y showed severe deficits resembling the null and was resistant to pan-neuronal, but responded to cholinergic neuron-restricted rescue, consistent with a dominant-negative effect on dNf1 dimerization. In contrast, dNf1R1861C presented a milder phenotype that was largely reversible by wild-type dNf1 but only partially by the GRD domain, implicating an additional, GRD-independent mechanism. Collectively, these findings define cholinergic neurons as the key circuit through which Neurofibromin regulates sleep consolidation via Ras/MAPK signaling and reveal mutation-specific mechanisms that mirror the phenotypic heterogeneity seen in NF1 patients, with implications for genotype-informed understanding of sleep disturbance in this disorder. Competing Interest Statement The authors have declared no competing interest. Funder Information Declared Children's Tumor Foundation , CTF-2022-05-004 United States Department of Defense, https://ror.org/0447fe631 , W81XWH-20-1-0255 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Back to top Previous Next Posted October 24, 2026. Download PDF Supplementary Material Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Neurofibromin Regulates Sleep Consolidation via Cholinergic Neurons in a Drosophila Model of Neurofibromatosis 1 Message Subject (Your Name) has forwarded a page to you from bioRxiv Message Body (Your Name) thought you would like to see this page from the bioRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share Neurofibromin Regulates Sleep Consolidation via Cholinergic Neurons in a Drosophila Model of Neurofibromatosis 1 Kalliopi Atsoniou , Eirini-Maria Georganta , Kathrin Pfeifer , Ruth Palmer , Martina Samiotaki , Efthimios MC Skoulakis bioRxiv 2026.10.20.760518; doi: https://doi.org/10.64898/2026.10.20.760518 Share This Article: Copy Citation Tools Neurofibromin Regulates Sleep Consolidation via Cholinergic Neurons in a Drosophila Model of Neurofibromatosis 1 Kalliopi Atsoniou , Eirini-Maria Georganta , Kathrin Pfeifer , Ruth Palmer , Martina Samiotaki , Efthimios MC Skoulakis bioRxiv 2026.10.20.760518; doi: https://doi.org/10.64898/2026.10.20.760518 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Areas All Articles Animal Behavior and Cognition (8164) Biochemistry (19027) Bioengineering (15171) Bioinformatics (45345) Biophysics (22958) Cancer Biology (20115) Cell Biology (27308) Clinical Trials (138) Developmental Biology (14146) Ecology (21400) Epidemiology (2067) Evolutionary Biology (25811) Genetics (16343) Genomics (23841) Immunology (19027) Microbiology (43196) Molecular Biology (18345) Neuroscience (95083) Paleontology (713) Pathology (3034) Pharmacology and Toxicology (5200) Physiology (8284) Plant Biology (16271) Scientific Communication and Education (2116) Synthetic Biology (4646) Systems Biology (10386) Zoology (2427)
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