SREBP modulates the NADP+/NADPH cycle to control night sleep in Drosophila

Vittoria Mariano, Alexandros K. Kanellopoulos, Giuseppe Aiello, Adrian C. Lo, Eric Legius, Tilmann Achsel and Claudia Bagni ()
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Vittoria Mariano: University of Lausanne
Alexandros K. Kanellopoulos: University of Lausanne
Giuseppe Aiello: University of Lausanne
Adrian C. Lo: University of Lausanne
Eric Legius: KU Leuven
Tilmann Achsel: University of Lausanne
Claudia Bagni: University of Lausanne

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Sleep behavior is conserved throughout evolution, and sleep disturbances are a frequent comorbidity of neuropsychiatric disorders. However, the molecular basis underlying sleep dysfunctions in neurological diseases remains elusive. Using a model for neurodevelopmental disorders (NDDs), the Drosophila Cytoplasmic FMR1 interacting protein haploinsufficiency (Cyfip85.1/+), we identify a mechanism modulating sleep homeostasis. We show that increased activity of the sterol regulatory element-binding protein (SREBP) in Cyfip85.1/+ flies induces an increase in the transcription of wakefulness-associated genes, such as the malic enzyme (Men), causing a disturbance in the daily NADP+/NADPH ratio oscillations and reducing sleep pressure at the night-time onset. Reduction in SREBP or Men activity in Cyfip85.1/+ flies enhances the NADP+/NADPH ratio and rescues the sleep deficits, indicating that SREBP and Men are causative for the sleep deficits in Cyfip heterozygous flies. This work suggests modulation of the SREBP metabolic axis as a new avenue worth exploring for its therapeutic potential in sleep disorders.

Date: 2023
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DOI: 10.1038/s41467-022-35577-8

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