PUBLICATION
Cross-species evidence for a developmental origin of adult hypersomnia with loss of synaptic adhesion molecules beat-Ia/CADM2
- Authors
- Mace, K., Zimmerman, A., Chesi, A., Doldur-Balli, F., Kim, H., Almeraya Del Valle, E., Rosa, J.B., Pack, A.I., Grant, S.F.A., Kayser, M.S.
- ID
- ZDB-PUB-260113-10
- Date
- 2026
- Source
- Nature communications : (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Brain/metabolism
- Cell Adhesion Molecules*/genetics
- Cell Adhesion Molecules*/metabolism
- Cell Adhesion Molecules, Neuronal*/genetics
- Cell Adhesion Molecules, Neuronal*/metabolism
- Connectome
- Disorders of Excessive Somnolence*/genetics
- Disorders of Excessive Somnolence*/metabolism
- Drosophila Proteins*/genetics
- Drosophila Proteins*/metabolism
- Drosophila melanogaster/genetics
- Female
- Humans
- Immunoglobulins*/genetics
- Immunoglobulins*/metabolism
- Male
- Neurons/metabolism
- Neuropeptides/genetics
- Neuropeptides/metabolism
- Sleep
- Species Specificity
- Synapses/metabolism
- Zebrafish/genetics
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 41526386 Full text @ Nat. Commun.
Citation
Mace, K., Zimmerman, A., Chesi, A., Doldur-Balli, F., Kim, H., Almeraya Del Valle, E., Rosa, J.B., Pack, A.I., Grant, S.F.A., Kayser, M.S. (2026) Cross-species evidence for a developmental origin of adult hypersomnia with loss of synaptic adhesion molecules beat-Ia/CADM2. Nature communications. :.
Abstract
Idiopathic hypersomnia (IH) is a poorly understood sleep disorder characterized by excessive daytime sleepiness despite normal nighttime sleep. Combining human genomics with behavioral and mechanistic studies in fish and flies, we uncover a role for beat-Ia/CADM2, synaptic adhesion molecules of the immunoglobulin superfamily, in excessive sleepiness. Neuronal knockdown of Drosophila beat-Ia results in sleepy flies and loss of the vertebrate ortholog of beat-Ia, CADM2, results in sleepy fish. We delineate a developmental function for beat-Ia in synaptic elaboration of neuropeptide F (NPF) neurites projecting to the suboesophageal zone (SEZ) of the fly brain. Brain connectome and experimental evidence demonstrate these NPF outputs synapse onto a subpopulation of SEZ GABAergic neurons to stabilize arousal. NPF is the Drosophila homolog of vertebrate neuropeptide Y (NPY), and an NPY receptor agonist restores sleep to normal levels in zebrafish lacking CADM2. These findings point towards NPY modulation as a treatment target for human hypersomnia.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping