Related Experiment Video
Updated: May 14, 2026
05:05
Establishing a Device for Sleep Deprivation in Mice
Published on: September 22, 2023
Peripheral metabolic dysfunction drives sleep disruption in TDP-43 proteinopathy
Anyara Rodriguez1, Samuel J Belfer1, Jenny Luong1
1Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
Biorxiv : the Preprint Server for Biology
|May 13, 2026
Summary
Neurodegenerative diseases like TDP-43 proteinopathy cause sleep loss due to peripheral metabolic dysfunction, not just brain issues. Restoring metabolic health, particularly through SIK3, can rescue sleep patterns.
Area of Science:
- Neuroscience
- Metabolic research
- Genetics
Background:
- Sleep disruption is an early symptom of neurodegenerative diseases.
- Current understanding attributes sleep loss to neuronal dysfunction or cell death.
- The link between metabolic state and sleep suggests systemic metabolic abnormalities could be involved.
Purpose of the Study:
- To investigate if peripheral metabolic dysfunction causally contributes to sleep disruption in TDP-43 proteinopathy models.
- To identify molecular mechanisms linking metabolic state and sleep loss.
Main Methods:
- Utilized *Drosophila* models of TDP-43 proteinopathy.
- Induced metabolic changes through genetic manipulation and dietary interventions.
- Conducted RNAi screening to identify genetic modifiers.
- Performed transcriptomic and spatial metabolomic analyses.
Main Results:
- TDP-43 expression induced a starvation-like metabolic state with depleted energy stores despite normal feeding.
- Sleep restoration drugs did not fix metabolic defects, but metabolic interventions rescued sleep.
- SIK3 was identified as a key suppressor of sleep loss and starvation sensitivity.
- SIK3 remodeled peripheral metabolism via the pentose phosphate pathway and redox metabolites.
Conclusions:
- Systemic metabolic dysfunction is a primary driver of sleep disruption in TDP-43 proteinopathy.
- Peripheral metabolism represents a potential therapeutic target for sleep disturbances in neurodegenerative diseases.
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